NZ616500B2 - Treatment of disease with poly-n-acetyglucosamine nanofibers - Google Patents
Treatment of disease with poly-n-acetyglucosamine nanofibers Download PDFInfo
- Publication number
- NZ616500B2 NZ616500B2 NZ616500A NZ61650012A NZ616500B2 NZ 616500 B2 NZ616500 B2 NZ 616500B2 NZ 616500 A NZ616500 A NZ 616500A NZ 61650012 A NZ61650012 A NZ 61650012A NZ 616500 B2 NZ616500 B2 NZ 616500B2
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- NZ
- New Zealand
- Prior art keywords
- snag
- snag nanofibers
- infection
- disease
- acetylglucosamine
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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Abstract
Discloses the use of a composition comprising shortened fibres of poly-?-1?4-N-acetylglucosamine (“sNAG nanofibers”) in the manufacture of a medicament for treating a viral infection or a viral disease in a human subject having a viral infection or a viral disease, wherein the treating comprises topically administering the composition comprising the sNAG nanofibres to the human subject, and wherein (i) more than 50% of the sNAG nanofibres are between about 1 to 15 ?m in length, or (ii) the average length of the sNAG nanofibres is less than 15 ?m. ically administering the composition comprising the sNAG nanofibres to the human subject, and wherein (i) more than 50% of the sNAG nanofibres are between about 1 to 15 ?m in length, or (ii) the average length of the sNAG nanofibres is less than 15 ?m.
Description
[0004a]In one , particularly herein is a use of a composition comprising shortened fibers of
poly-β-1→4-N-acetylglucosamine and/or derivatives thereof (“sNAG nanofibers”) in the manufacture
of a medicament for treating a viral infection or a viral disease in a human t having a viral
infection or a viral disease, wherein the treating comprises topically administering the composition
comprising the sNAG nanofibers to the human subject, and wherein (i) more than 50% of the sNAG
nanofibers are between about 1 to 15 µm in , or (ii) the average length of the sNAG nanofibers
is less than 15 µm.
1 (followed by 1A)
[0004b]In another aspect, particularly described herein is a use of a composition comprising
shortened fibers of poly-β-1→4-N-acetylglucosamine and/or derivatives f (“sNAG nanofibers”)
in the manufacture of a medicament for preventing a viral disease in a human subject at risk of
ping a viral disease, wherein the treating comprises topically administering the composition
comprising sNAG nanofibers to the human t, and wherein (i) more than 50% of the sNAG
nanofibers are between about 1 to 15 µm in length, or (ii) the average length of the sNAG nanofibers
is less than or (ii) the average length of the sNAG bers is less than 15 µm.
[0004c] Other aspects are described herein for completeness and may form the subject of one or more
divisional applications.
1A (followed by 2)
WO 42581
administering a ition sing sNAG nanofibers to a subject at risk of developing a
viral disease (e.g., a symptom of an HSV infection such as a cold sore or a lesion). In a specific
embodiment, the sNAG nanofiber composition is topically administered to the t (e.g., to
the skin or mucous membrane). In specific embodiments, the subject is a human.
In another ment, described herein is a method for treating a solid tumor in a
subject, comprising administering a composition comprising sNAG nanofibers to a subject
diagnosed with a solid tumor. In a specific embodiment, all or part of the solid tumor has been
removed from the subject (e.g., ally removed), and the sNAG nanofibers are administered
to the site of the solid tumor , during, and/or after the l of all or part of the solid
tumor. In Specific embodiments, the subject is a human.
In another embodiment, described herein is a method for treating a skin cancer in a
subject, sing topically administering a composition comprising sNAG nanofibers to a
human subject diagnosed with a skin cancer. In a specific embodiment, all or part of the skin
cancer has been removed from the subject (e. g., surgically removed), and the sNAG nanofibers
are administered to the site of the skin cancer before, during, and/or after the removal of all or
part of the skin cancer. In specific embodiments, the subject is a human.
In another embodiment, provided herein is a method for treating inflammatory bowel
disease in a subject, comprising administering a composition comprising sNAG nanofibers to a
subject with inflammatory bowel disease (e.g., diagnosed with inflammatory bowel disease). In
a specific embodiment, described herein is a method for treating Crohn’s disease in a subject,
comprising administering a composition comprising sNAG nanofibers to a subject with Crohn’s
e (e.g., a subject diagnosed with Crohn’s disease). In a specific embodiment, the sNAG
nanofiber ition is topically administered to the subject (e.g., rectally via a suppository).
In specific embodiments, the subject is a human.
The sNAG nanofibers contemplated in the methods described herein may be of
varying lengths, widths and molecular weights as described in n 5.1, infra. In certain
embodiments, the ty (and in certain embodiments, at least or more than 60%, 70%, 80%,
90%, 95% or 99%) of the sNAG nanofibers, or 100% of the sNAG nanofibers, are between
about 1 to 15 um in length. In some embodiments, the majority (and in certain embodiments, at
least or more than 60%, 70%, 80%, 90%, 95% or 99%) of the sNAG nanofibers, or 100% of the
sNAG ers, are between about 2 to 10 pm, 4 to 7 pm, 4 to 10 pm, or 5 to 10 pm in length.
The sNAG nanofibers of the bed length can be obtained, for example, as described below
in n 5.2, infra.
In certain embodiments, the sNAG nanofibers were produced by irradiation, e.g.,
gamma irradiation, of poly-N-acetylglucosamine or a derivative thereof. In some embodiments,
the sNAG nanofibers are produced by irradiation of the poly-B—I-—>4-N-acetylglucosamine in the
form of dried fibers (e.g., at SOD-2,000 kgy), or irradiation of the poly-[S-l-a4-N-
acetylglucosamine in the form of wet fibers (e.g., at 100-500 kgy).
In certain embodiments, the sNAG nanofibers are derived from microalgae. In
another embodiment, the sNAG nanofibers are not derived from crustaceans. In yet another
embodiment, the sNAG nanofibers may be d from microalgae, crustaceans (e.g., ),
fungus or any other source,
In one embodiment, the sNAG nanofibers comprise ylglucosamine
monosaccharides and/or glucosamine monosaccharides, wherein more than 60%, 70%, 80%,
90%, 95%, or 99% of the monosaccharides of the sNAG ers are N-acetylglucosamine
monosaccharides. In another embodiment, the sNAG nanoflbers comprise N-acetylglucosamine
monosaccharides and/or glucosamine monosaccharides, wherein more than 70% of the
monosaccharides of the sNAG nanoflbers are N-acetylglucosamine monosaccharides.
In certain embodiments, the sNAG nanofibers used in the s described
herein are non-reactive in a biocompatibility test or tests. For example, the sNAG nanofibers
used in the methods described herein may be non-reactive when tested in an n test, an
intramuscular implantation test, an intracutaneous test, or a systemic test. In some embodiments,
the compositions described herein are non-reactive when tested in an elution test, an
intramuscular implantation test, an intracutaneous test, or a systemic test. In other embodiments,
the sNAG nanofibers used in the methods described herein have Grade 0 or Grade 1 when tested
in an elution test, an intramuscular implantation test, an intracutaneous test, or a ic test. In
yet another embodiment, the sNAG nanofibers used in the methods described herein are at most
mildly ve when tested in an elution test, an intramuscular implantation test, an
intracutaneous test, or a systemic test. In one embodiment, the sNAG nanofibers or
itions comprising such nanofibers are non-reactive as determined by an intramuscular
implantation test. In certain embodiments, the compositions described herein do not cause an
allergenic reaction or an irritation, e.g., at the site of application. In other embodiments, the
compositions bed herein cause at most a mild allergenic on or a mild irritation, e.g.,
at the site of ation.
In certain embodiments, the sNAG nanofibers used in the methods described
herein se the lic rate of serum-starved human umbilical cord vein endothelial cells
in a MTT assay and/or do not rescue apoptosis of serum—starved human umbilical cord vein
endothelial cells in a trypan blue exclusion test. In some embodiments, the sNAG nanofibers
increase the metabolic rate of serum-starved human umbilical cord vein endothelial cells in a
MTT assay and do not rescue apoptosis of serum—starved human umbilical cord vein endothelial
cells in a trypan blue exclusion test.
The contemplated modes of administration of the compositions described herein
are topical, e.g., topical on the skin; topical at the site of a wound, a surgery, a viral infection, a
fungal infection, or a symptom of an infection (e.g., a swelling, a blister, a rash, a ); and
topical to a body surface such as the skin, mucous membranes (e.g., vagina, anus, throat, eyes,
ears), or the surface of other tissues. In certain embodiments, the sNAG bers or
compositions sing such nanofibers are formulated as a dressing, a bandage, a mat, a spray,
a liquid, 3 suspension (e.g., a thick suspension), a membrane, a powder, an ointment, a cream, a
paste, a suppository, or a gel. In some embodiments, the sNAG nanoflbers or compositions
comprising such nanofibers are formulated as a suspension, a cream, a liquid solution, a gel, an
ointment, a membrane, a powder, a spray, or a suppository. In one embodiment, the sNAG
nanofibers or compositions comprising such nanofibers are formulated as a suspension (e.g., a
thick suspension). In particular embodiments, compositions comprising the sNAG nanofibers
are not solid or barrier—forming.
In another aspect, described herein are compositions for use in the methods
described herein. In a specific embodiment, the compositions comprise sNAG bers‘. In
n embodiments, the compositions described herein comprise sNAG nanofibers and one or
more additional active ingredients useful in preventing and/or treating solid tumor s, skin
cancer, viral infections, viral es, yeast infections, fungal infections, fungal es,
inflammatory bowel disease, Crohn’s disease, dermatitis and psoriasis. In certain embodiments,
the itions described herein do not comprise any additional anti-bacterial agent (e. g., an
antibiotic). In a specific embodiment, the compositions described herein comprise the sNAG
nanofibers as the only active ingredient and do not se any additional active ingredients.
2012/033782
In certain embodiments, the compositions bed herein are stered in
conjunction with one or more additional therapies. In other embodiments, the compositions
described herein are not administered in conjunction with any other therapy.
3.1 Terminology
As used herein, the terms “sNAG nanofiber,” “sNAG,” “Taliderm,” or “Talymed”
(formerly known as “Taliderm”) are used interchangeably to refer to shortened fibers of -
acetylglucosamine and/or derivatives thereof. In a preferred embodiment, sNAG nanofibers
t entirely of shortened fibers of poly-N-acetylglucosamine and/or derivatives thereof.
Taliderm or Talymed are examples of sNAG nanofibers which are membranes consisting
entirely of shortened fibers of poly-N-acetylglucosamine and/or derivatives thereof.
As used herein, the term ” means a range around a given value wherein the
resulting value is the same or substantially the same (e.g., within 10%, 5% or 1%) as the
expressly recited value. In one embodiment, “about” means within 10% of a given value or
range. In another embodiment, the term ” means within 5% of a given value or range. In
r embodiment, the term “about” means within 1% of a given value or range.
As used herein, the terms se” and “disorder” are used interchangeably to refer
to a condition in a subject. Exemplary diseases/disorders that can be treated or prevented in
accordance with the methods described herein include, without limitation, solid tumor cancers,
skin s, viral diseases, yeast diseases, fungal diseases, inflammatory bowel disease, and
Crohn’s disease, psoriasis and dermatitis. In the t of viral diseases, yeast diseases, and
fungal diseases, the disease is the pathological state resulting from infection by a virus, a yeast,
or a fungis, respectively.
. As used herein, the term “infection” means the invasion by, multiplication and/or
presence ofa pathogen (e.g., a virus, yeast, or ) in a cell or a subject.
As used herein, the numeric term “log” refers to logo.
As used herein, the term “subject” and “patient” are used interchangeably to refer to
an animal (e.g., cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea
pig, etc). In some embodiments, the subject is a mammal such as a non—primate and a primate
(e.g., monkey and human). In specific embodiments, the subject is a human.
As used herein, the term “effective amount” in the context of administering a sNAG
nanofiber or composition thereof to a subject refers to the amount of a sNAG nanofiber or
ition thereof that results in a beneficial or therapeutic effect. In specific embodiments, an
“effective amount” of a sNAG nanofiber or composition thereof refers to an amount of a sNAG
nanofiber or composition f which is sufficient to achieve at least one, two, three, four or
more of the following effects: (i) reduction or amelioration of the severity of a disease in the
subject or population of subjects or a symptom associated therewith; (ii) ion of the
duration of a disease in the subject or population of subjects or a symptom associated ith;
(iii) prevention of the ssion of a disease in the subject or population of subjects or a
symptom ated therewith; (iv) regression of a disease in the subject or population of
subjects or a symptom associated therewith; (v) prevention of the development or onset of a
disease in the subject or population of subjects or a symptom associated therewith; (vi)
prevention of the recurrence of a e in the subject or population of subjects or a symptom
associated therewith; (vii) prevention or reduction of the spread of a e from the subject or
population of subjects to another subject or population of subjects; (viii) ion in organ
failure associated with a disease in the subject or population of subjects; (ix) reduction of the
incidence of hospitalization of the subject or population of-subjects; (x) reduction of the
hospitalization length of the subject or population of subjects; (xi) an increase the survival of the
subject or population of ts; (xii) elimination ofa disease in the subject or population of
subjects; (xiii) enhancement or improvement of the prophylactic or therapeutic effect(s) of
r therapy in the subject or population of subjects; (xiv) prevention of the spread of a
pathogen from a cell, tissue, organ of the subject to another cell, , organ of the subject; (xv)
reduction of the number of symptoms of a disease in the subject or population of ts; (xvi)
the clearance of an infection with a pathogen (e.g., a virus, a fungus, or an yeast); (xvii) the
eradication of one or more symptoms associated with an infection; (xviii) the reduction of time
required to clear an infection; (xix) the reduction of time required to clear an infection; (xx) the
reduction or amelioration of the ty of an infection and/or one or more symptoms associated
therewith; (xxi) the prevention of the recurrence of an infection and/or one or more ms
associated there with; (xxii) the reduction or elimination of a pathogen as measured, e. g., by viral
count; (xxiii) the ion or elimination in the spread of a pathogen from one subject to another
subject, or one organ or tissue to r organ or ; (xxiv) the prevention of an increase in
the pathogen numbers as measured, e.g., by viral count; (xxv) the prevention of the development
or onset of an infection or one or more symptoms associated ith; (xxvi) the reduction in
the number of symptoms ated with an infection; (xxvii) the stabilization or reduction of
inflammation associated with an infection; (xxviii) the induction of the expression of one or
more defensin proteins and/or defensin-like proteins; (xxix) the induction of the expression of
one or more Toll—like receptors; (xxx) the induction of the expression of one or more proteins
that are beneficial for clearance or reduction of a pathogen infection or one or more symptoms
associated therewith; (xxxi) the reduction in organ e ated with a pathogen infection or
a disease associated therewith; (xxxii) the prevention of the onset, development or recurrence of
a condition caused by or associated with a pathogen infection; (xxxiii) the reduction in ity;
(xxxiv) the inhibition of the progression of a cancer and/or one or more symptoms associated
therewith; (xxxv) a reduction or elimination in the cancer cell population; (xxxvi) a ion in
the growth of a tumor or sm; (xxxvii) a decrease in tumor size (e.g., volume or diameter);
(xxxvii) a reduction in the ion of a newly formed tumor; (xxxviii) eradication, removal, or
control of primary, al and/or metastatic cancer; (xxxix) a decrease in the number or size of
metastases; (xxxx) an se in tumor-free survival rate of ts; (xxxxi) an increase in
relapse free survival; (xxxxii) an increase in the number of patients in ion; (xxxxiii) the
size ofa tumor is maintained and does not increase or increases by less than the‘increase ofa
tumor after administration of a standard therapy as measured by conventional methods available
to one of skill in the art, such as evaluation of PSA concentrations, digital rectal exam,
ultrasound (e.g., ectal ultrasound), bone scan, computed tomography (CT) scan, magnetic
resonance imaging (MRI), dynamic st-enhanced MRI (DCE-MRI), or a positron emission
tomography (PET) scan; (xxxxiv) an se in the length of remission in patients; (xxxxv) an
increase in symptom-free survival of cancer ts; (xxxxvi) stabilization or reduction of a
tumor or peritumoral inflammation or edema; (xxxxvii) inhibition or decrease in tumor
metabolism or perfusion; and/or (xxxiii) improvement in quality of life as assessed by methods
well known in the art, e.g., a questionnaire. In specific embodiments, an “effective amount" of a
sNAG nanofiber refers to an amount of a sNAG nanofiber composition specified herein, e.g., in
Section 5.6, infra.
As used herein, the term “premature human infant” refers to a human infant born at
less than 37 weeks of gestational age.
As used herein, the term “human infant” refers to a newborn to 1 year old human.
As used herein, the term “premature human infant” refers to a newborn to 1 year old
year human who was born of less than 37 weeks gestational age (e.g., before 37 weeks, 36
weeks, 35 weeks, 34 weeks, 33 weeks, 32 weeks, 31 weeks, 30 weeks, 29 weeks, 28 weeks, or
less than 28 weeks of pregnancy).
As used herein, the term “human toddler” refers to a human that is 1 years to 3 years
old.
As used , the term “human child” refers to a human that is 1 year to 18 years
old.
As used herein, the term “human adult” refers to a human that is 18 years or older.
As used , the term “elderly human” refers to a human 65 years or older.
As used herein, the term “low expression,” in the context of expression of a gene
(e.g., based on the level of protein or peptide produced by the gene) refers to an sion that
is less than the “normal” expression ofthe gene. In a specific embodiment, “low sion”
refers to expression of a gene that is less than 99%, less than 95%, less than 90%, less than 85%,
less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less
than 45%, less than 40%, less than 35%, less than 30%, less than 25%, or less than 20% ofthe
“normal” expression of the gene. In another specific embodiment, “low expression” refers to
expression of a gene that is about 20-fold, about 15-fold, about 10-fold, about 5-fold, about 4-
fold, about 3—fold, about 2-fold, or about 1.5 fold less than the “normal” expression of the gene.
As used herein, the term “majority” refers to r than 50%, including, e.g., 50.5%,
51%, 55%, etc.
As used herein, the terms “therapies” and py” can refer to any protocol(s),
method(s), compositions, formulations, and/or agent(s) that can be used in the prevention and/or
treatment of an infection with a pathogen or a disease or a symptom thereof, or a disease
described herein (such as Crohn’s disease, inflammatory bowel disease, psoriasis, dermatitis, and
solid tumor). A pathogen may be a virus, a fungus, or an yeast. In certain embodiments, the
terms “therapies” and “therapy” refer to drug therapy, nt therapy, radiation, surgery,
biological therapy, supportive therapy, and/or other therapies useful in treatment and/or
tion of an infection with a pathogen or a e, or a symptom thereof, or a disease
described herein. In certain embodiments, the term “therapy” refers to a therapy other than a
sNAG nanofiber or a pharmaceutical composition thereof. In specific embodiments, an
“additional therapy” and ional therapies” refer to a therapy other than a treatment using a
sNAG nanofiber or a ceutical composition thereof. In a specific embodiment, a therapy
includes the use of a sNAG nanofiber as an adjuvant y. For e, using a sNAG
nanofiber in conjunction with a drug therapy, biological therapy, surgery, and/or supportive
therapy;
4. BRIEF DESCRIPTION OF FIGURES
Figure l. Nanofibers stimulate Akt 1 activation, an upstream regulator of Etsl. (A)
Western blot is of phospho-Akt in response to NAG and sNAG stimulation of serum
starved EC. (B) RT-PCR analysis of EC infected either with scrambled control (“SCR”) or Aktl
shRNA lentiviruses and assessed for expression of Etsl and $26 as a loading control. (C)
Schematic of a signal transduction y transducing a signal from sNAG nanofibers to Aktl,
Etsl and Defensins.
Figure 2. Delayed wound g in Akt] null animals is partially d by
rm treatment. (A) Representative images of wounded WT and AKTl null mice with and
without treatment of Taliderm. (B) H&E staining of representative mouse skin sections from
day 3 wounds.
Figure 3. sNAG nanofibers stimulate cytokine and defensin expression in primary
endothelial cells. (A) Immunohistochemisty of EC treated with or without sNAG using an
antibody directed against a-defensin. (B) ELISA g that nanofiber treatment of EC results
in the secretion of a-defensins 1-3 (serum starved, treated with 5 ug/ml or 10 ug/ml sNAG).
Figure 4. sNAG ers stimulate defensin expression in primary endothelial
cells in an Aktl dependent manner. (A) and (B) Quantitative RT-PCR analyses of serum starved
EC (“55”) treated with or without sNAG (“snag”), with or without PD98059 (MAPK inhibitor,
“PD”), Wortmannin (PI3K inhibitor, “wtm”) or infected with a scrambled control (“SCR”), or
Aktl (“AKTl”) shRNA lentiviruses and assessed for expression of the genes indicated.
Figure 5. sNAG nanofibers ate B-defensin 3 expression in mouse
keratinocytes. (A) Immunofluorescent staining with B-defensin 3 (visible as bright staining in
the upper right hand panel; see, e.g., thick white arrows) and Involucrin antibodies of paraffin
embedded mouse cutaneous wound ns from WT and Akt] null animals on Day 3. (B)
Quantification of B-defensin 3 immunofluorescent staining using NIHImageJ software
(TX=Talidemi; Aktl=Aktl null). (C) fluorescent staining of WT and Aktl null treated
and untreated keratinocytes with B-Defensin 3 (visible as bright staining; see, e.g., thick white
arrows) and TOPRO-3 (nuclei staining; see, e.g., thin white arrows). Notice the se in BDefensin
3 staining in WT and Aktl rm treated wounds.
Figure 6. Aktl dependent transcription factor binding sites. Schematic of Aktl
dependent transcription factor binding sites. Using Genomatix software, 500 bp upstream of the
transcription start site was ed for conserved sites on the mRNA of DEF], 4, and 5 (ETS-
black ovals; FKHD-striped ovals; CREB-white ovals; NFKB-checkered ovals).
Figure 7. sNAG treatment results in expression and secretion of defensins in .vitro.
(A) RTPCR analysis of serum starved (“SS”) primary endothelial cells treated with sNAG
(SOpg/ml) for the times indicated and ed for expression of B-defensin 3 and fensin l.
(B) Immunofluorescent labeling of elial cells either serum starve-d (untreated) or treated
with sNAG nanofibers (IOug/ml for 5hrs). Antibodies are directed against a—defensin 5 (FlTC,
upper left hand panel), B—defensin 3 (Texas Red, upper right hand panel). Nuclei are stained with
TOP‘RO-3 (Blue, lower left hand . Lower right hand panel represents triple overlay. (C)
lmmunofluorescent labeling of keratinocytes (HaCat) that are either serum starved (untreated) or
treated with sNAG nanofibers (lOug/ml for 5 . Antibodies are directed against (it-defensin
(FITC, upper left hand panel), [El—defensin 3 (Texas Red, upper right hand panel). Nuclei are
stained with TOPRO-3 (Blue, lower left hand panel).
Figure 8. sNAG induced defensin expression is dependent on Aktl. (A)
Quantitative RT-PCR analyses using primers directed against tit-defensin 1 from total RNA
isolated from serum starved endothelial cells treated with or without sNAG for 3 hours, with or
without pretreatment with FD098059 (50pM), wortmannin (“WTM”)(100nm).
Quantitation is relative to the 826 protein subunit. (B) Quantitation of B-defensin 3 expression
from total RNA isolated from serum starved endothelial cells treated with or without sNAG for 3
hours, with or without 9 (50pm), wortmannin (100nm) and shown as relative to 826. (C)
Western Blot analysis of phospho—Akt in serum starved endothelial cells (SS) stimulated with
sNAG for the times ted. Line indicates where lanes have been removed (D) Quantitative
RT-PCR analyses of serum starved elial cells infected with a scrambled control (SCR) or
Aktl shRNA lentiviruses, treated with or without sNAG and assessed for (it-defensin 4
expression. Quantitation is shown relative to 826. (E) Quantitation of B-defensin 3 expression
from total RNA isolated from serum starved endothelial cells infected with a led control
(SCR) or Aktl shRNA lentiviruses, treated with or without sNAG. Quantitation is shown
relative to 826. All experiments were done in at least triplicate and repeated at least three
independent times and p values are shown.
Figure 9. sNAG induced defensin expression in viva es Aktl. (A) Paraffin
embedded sections of cutaneous wounds harvested on day 3 post wounding from both WT (n=3)
and Aktl mice. Wounds were either untreated or treated with sNAG membrane.
Immunofluorescence was performed using antibodies directed against B—defensin 3 (green,
e as bright staining in the upper right hand panel; see, e.g., white thick arrows), Involucrin
(Red), and Topro (Blue, nuclei staining; see, e.g., white thin arrows). (B) n embedded
section from WT treated with sNAG harvested on day 3. Immunofluorescence was performed
using antibodies directed against [3- defensin 3 (green, visible as bright staining; see, e.g., thick
white arrows), Involucrin (Red), and Topro (Blue, nuclei staining; see, e.g., thin white ).
This lower magnification (20x) is included to better illustrate the epidermal layers expressing [3—
defensin 3. Scale bars = 50 pm. (C) Quantitation of B-defensin 3 expression from paraffin
embedded sections was performed using NIH Image] software. ments were repeated three
independent times and p values are shown.
Figure 10. sNAG treatment increases wound closure in wild type mice. H&E
staining of wound tissue sections derived from C57Bl6 wild type animals either untreated or
treated with sNAG membrane. The day post-wound is ted to the left of each panel. The
solid black line follows the keratinocyte cell layer indicating wound e. Black arrows
indicate the margin of the wound bed.
Figure 11. sNAG treatment reduces ial infection in an Aktl dependent
manner. (A) Tissue gram staining of S. aureus ed wounds from WT mice. WT mice were
wounded using a 4 mm biopsy punch. Immediately after wounding mice were inoculated with l
x 109 cfu/ml. 30 minutes post—infection, mice in the treated group were treated with Taliderm.
Skin samples were taken 5 days post-treatment and sectioned for analysis. Tissue gram staining
was performed. Dark purple staining indicates gram-positive bacteria and phils that have
engulfed bacteria. 'Sections under 20x and 40x magnification are shown. (B) Tissue gram
staining of paraffin embedded S. aureus infected wounds from WT and Aktl null mice (n=3).
Infected wounds were either ted or treated with sNAG membrane and wound beds were
ted on day 3 and day 5 for analysis. Dark purple staining indicates the presence of gram
positive ia in the wound bed. Black arrows indicate examples of gram positive staining. .
Note the accumulation of positive staining in untreated WT that is lacking in WT animals treated
with sNAG. Scale bars = 50pm. (C) CFUs derived from day 5 post wounding were quantitated
from S. aureus infected wounds using both d and untreated WT (n= 3) and Aktl mice
(n=3). Wild type mice that were sNAG treated show a significant ) decrease in bacteria
load in the wound.beds as ed to Aktl null animals. All ments were repeated three
independent times and the p values are shown. (D) CFU quantitated from infected wounds at
day 3 post wounding in a similar n described in (C). sNAG treatment of infected wounds
shows a significant decrease in CFU of both WT and Aktl null animals on day 3, but the WT
animals show an approximate 10 fold difference compared to a 2 fold difference in Aktl
animals. (E) Quantitation of CFUs in S. aureus cultures that were either untreated or treated with
various amounts-of sNAG nanofibers. Each experiment was performed three independent times
and p values are shown. (F) Tissue gram staining of S. aureus infected wounds harvested on day
3 post wound from WT mice (n=3) that were treated with or without [5- defensin 3 peptide (1.0
uM). Note the decrease in gram positive ng in infected wounds that were treated with B-
defensin 3 peptide. (G) Quantitation of CFUs from S. aureus ed WT mice (n=3) treated
with or without B-defensin 3 peptide. ed wounds that were treated with peptide show a
significant decrease (p <.05) in CFU. Scale bars = 50pm. Each experiment was performed three
independent times and p values are shown.
Figure 12. Rapid induction of defensin expression by sNAG ent of S. aureus
infected wounds. (A) Paraffin embedded tissue sections from S. aureus infected ,
harvested on day 3, were subjected to fluorescence using antibodies directed against [3-
defensin 3 (green, visible as bright staining in the upper right hand panel and in the lower panel
in the middle; see, e.g., thick white arrows), Involucrin (red) to mark the keratinocyte layer, and
Topro (blue, nuclei staining; see, e.g., thin white arrows) from both sNAG treated WT (n=3) and
untreated WT mice (n=3). Non specific staining of keratin is indicated by the no primary control
which was stained with secondary antibody only. Scale bar = 50pm. (B) Quantitation of B-
defensin 3 expression from paraffin embedded sections using NIH Image] software. S. aureus
infected wounds that were treated with sNAG show a significant increase (p<.05) in B—defensin 3
ng. Experiments were repeated three independent times and p values are shown.
Figure 13. dies against B-defensin 3 s antibacterial effects of sNAG
treatment. (A) Tissue gram staining of in embedded S. aureus infected wounds d
with sNAG from WT mice (n=3) that were harvested on Day 3. sNAG treated wounds were
treated with either B-defensin 3 antibody or isotype control goat lgG antibody prior to sNAG
treatment. Representative images show increased accumulation gram ve staining (black
arrows) in the wound beds of mice treated with an antibody directed against B—defensin 3. Scale
bar = 20pm. (B) Quantitation of CFUs from S. aureus infected WT mice treated either [3-
defensin 3 antibody (n=3) or control lgG dy (n=3) prior to sNAG treatment. B-defensin 3
application significantly increased (p <.05) CFU.
Figure 14. Effect of ation on chemical and physical structure of poly-N-
acetylglucosamine (“pGlcNAc”) fibers. (A) Correlation between molecular weight of pGlcNAc
and ation level/formulation for irradiation. (B) Infrared (IR) spectrum of radiated
pGlcNAc slurry (top line), pGlcNAc slurry irradiated at 100 kGy (bottom line), and pGlcNAc
slurry irradiated at 200 kGy (middle line). (C) Scanning electron microscopic (SEM) analyses of
pGlcNAc. .(D) Scanning electron microscopic (SEM) analyses of sNAG.
Figure 15. pGlcNAc did not affect metabolic rate. For each time period (i.e., at 24
and 48 hours), the identity for each of the four bars (from left to right) is as follows: serum
starvation (SS), VEGF, and pGlcNAc (NAG) at 50 and 100 ug/ml.
Figure 16. pGlcNAc protected human umbilical vein endothelial cell (EC) from cell
death induced by serum deprivation. For each time period (i. e., at 24, 48 and 72 hours), the
ty for each of the five bars (from left to right)‘is as s: serum starvation (SS), VEGF,
and pGlcNAc (NAG) at 50, 100, and 250 ug/ml.
Figure 17. sNAG induced marked increase in metabolic rate. Identity for each of the
five bars (from left to right) is as follows: serum starvation (SS), VEGF, and sNAG at 50, 100
and 200 ug/ml.
Figure 18. sNAG did not protect EC from cell death induced by serum deprivation.
For each time period (i.e., at 24 and 48 hours), the identity for each ofthe five bars (from léft to
right) is as follows: serum starvation (SS), VEGF, and sNAG at 50, 100 and 200 ug/ml.
Figure 19. Numeric Pain Intensity Scale.
Figure 20. Schematic showing experimental set up for the 3% D88 (dextran sodium
te)-induced inflammatory bowel e (in particular, ulcerative s) in a mouse
model.
Figure 21. sNAG treatment decreased inflammation in an animal model of
inflammatory bowel disease. (A) H&E staining of a section of intestinal epithelium from a
control group of 10 mice administered 3% D88 via ng water for 7 days (day 0 to day 7),
and saline via rectal suppository at day 0 and day 3 (100 pl). (B) H&E staining of a section of
intestinal epithelium from a test group of 10 mice administered 3% D88 via drinking water for 7
days (day 0 to day 7), and sNAG via rectal suppository at day 0 and day 3 (100 pl total with 12
pg/pl sNAG). Thin arrow and bracket point to the site of edema, and thick arrow points to the
site of leukocytic infiltration.
Figure 22. sNAG treatment decreased s in an animal model of atory
bowel disease. (A) staining for s of a section of intestinal epithelium from a control group
of 10 mice administered 3% DSS via drinking water for 7 days (day 0 to day 7), and saline via
rectal suppository at day 0 and day 3 (l00 pl). (B) staining for fibrosis of a section of intestinal
epithelium from a test group of 10 mice administered 3% D88 via drinking water for 7 days (day
0 to day 7), and sNAG via rectal suppository at day 0 and day 3 (100 p1 total with lZpg/pl
sNAG).
. DETAILED DESCRIPTION
The inventors of the present invention have found that sNAG nanofibers can
stimulate expression of defensins, which may boost the innate immune response. It is widely
accepted that defensins are important s in innate immunity. As demonstrated in the.
examples presented in Sections 6.1 and 6.2, infra, the inventors of the present invention have
found that sNAG nanofibers can se the expression of both a- and [3- type defensins in
endothelial cells and B-type defensins in keratinocytes in vitro and in a wound healing model in
vivo.
Further, as demonstrated in the examples presented in Sections 6.1 and 6.2, infra, but
without being bound by any specific mechanism of action, Aktl s to be important for
sNAG-dependent defensin expression in vitro and in vivo, in a wound healing model.
The ors of this invention have also found that a number of Toll-like receptors
can be up-regulated by sNAG treatment of human endothelial cells. Toll-like receptors (“TLRs”
or “TLR”) are highly conserved receptors that activate innate ty. Recent work has linked
human in expression to TLR activation, in particular, stimulation of TLR5 can lead to
increased defensin synthesis. Thus, without being bound by any mechanism of action, sNAG
nanofibers may act as a stimulator of innate immunity.
Accordingly, bed herein is the use of sNAG nanofibers as a novel method for
preventing and/or treating of infections and diseases for which an increase in sion and/or
secretion of one or more of defensins and Toll-like receptors may be beneficial. In certain
embodiments, treatment of viral, yeast or f1ingal infections with anofibers decreases the
pathogen count in patients. In specific embodiments, the use of sNAG nanofibers enhances
wound closure while aneously eradicating, decreasing or preventing a viral, a fungal or an
yeast infection of the wound. In other embodiments, the sNAG nanoflbers can be used in
treating a dermatological condition such as dermatitis or psoriasis by, for example, alleviating
one or more symptoms of such diseases. In yet another embodiment, the sNAG nanofibers can
be used in treating an Inflammatory Bowel Disease (e.g., Crohn’s disease) by, for example,
alleviating one or more symptoms of such diseases.
The inventors have, in fact, found that sNAGVnanofibers can be effective to treat viral
infections. In particular, the inventors found that sNAG nanoflbers are effective to treat HSV
infection when stered topically to human patients. e 8, infra, demonstrates that
topical administration of sNAG nanofibers to cold sores reduces the pain associated with cold
sores and reduces the duration of the cold sores in human ts. Cold sores are typically
caused by HSV-l infection, Thus, described herein are uses of sNAG nanofibers to treat viral
infections, in particular, topical viral infections. In specific embodiments, described herein are
uses of sNAG nanofibers to treat an HSV infection, or to treat and/or t a m
associated with an HSV infection (e.g., a cold sore or a lesion) by topical administration of
sNAG ers to a patient (e.g., at the site of HSV ion or the site ofa symptom of HSV
infection, or at the site where a symptom of infection is known to occur).
The inventors have also found that sNAG nanofibers can be effective to treat
inflammatory bowel disease (IBD). In particular, the inventors found that sNAG nanofibers are
effective to treat IBD in an animal model of IBD when administered rectally (such as via a
suppository). Example 9, infra, demonstrates that administration of sNAG nanofibers reduces
inflammation and fibrosis associated with IBD in a mouse model ofIBD. Thus, described herein
are uses of sNAG nanofibers to treat IBD, such as ulcerative colitis and Crohn’s disease. In
specific embodiments, described herein are uses of sNAG nanofibers to treat IBD (e.g.,
ulcerative colitis, or Crohn’s disease) by l administration of sNAG nanofibers to a patient
(e.g., to the anus or rectally via a suppository, a cream, a suspension, a liquid solution, a gel, or
an ointment).
.1 sNAG Nanofibers
Described herein are sNAG nanofiber compositions. The sNAG nanofibers comprise
fibers of poly-N-acetylglucosamine and/or a derivative(s) thereof, the majority of which are less
than 30 microns in length and at least 1 micron in length as measured by any method known to
1 one skilled in the art, for example, by ng on microscopy ). Such sNAG
nanofibers may be obtained, for example, as described herein.
In certain embodiments, the majority (and in certain embodiments, at least 60%, 70%,
80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to
75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) ofthe
sNAG ers are less than about 30, 25, 20, 15, 12, 10, 9, 8, 7, 6, 5, 4, or 3 microns in
, and at least 1 micron in length as measured by any method known to one skilled in the
art, for example, by SEM. In c embodiments, the majority (and in certain embodiments,
at least 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between
55% to 65%, 55% to 75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or
95% to 99%) of the sNAG nanofibers are less than about 15 microns or less than about 12
microns in length, and at least 1 micron in length as measured by any method known to one
d in the art, for example, by SEM. 1n specific embodiments, all (100%) ofthe sNAG
nanofibers are less than about 15 microns or less than about 10 microns in length, and at least 1
micron in length as measured by any method known to one skilled in the art, for example, by
SEM. In certain embodiments, the majority (and in certain embodiments, at least 60%, 70%,
80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to
75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) of the
sNAG nanofibers are equal to or less than 14, 13, 12, ll, 10, 9, 8 or 7 microns in length, and at
least 1 micron in length as ed by any method known to one skilled in the art, for example,
by SEM. In some embodiments, the majority (and in certain embodiments, at least 60%, 70%,
80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to
WO 42581
75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) ofthe
sNAG nanofibers are between 1 to 15, 2 to 15, 2 to 14, l to 12, 2 to 12, l to 10, 2 to 10, 3 to 12,
3t010,4to12,4t010,5to_12,5to10,1to9,2to9,3t09,lt08,2t08,3t08,4t08,1t07,
2 to 7, 3 to 7, 4 to 7, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 microns in length as measured by any method
known to one skilled in the art, for example, by SEM.
In a specific embodiment, the majority (and in certain embodiments, at least 60%,
70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%,
55% to 75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to
99%) of the sNAG nanofibers are about 8, 7, 6, 5, 4, 3 or 2 microns in.length as ed by any
method known to one skilled in the art, for example, by SEM. In another specific embodiment,
the ty (and in n embodiments, at least 60%, 70%, 80%, 90%, 95%, 98%, 99%,
99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to 75%, 65% to 75%, 75% to
85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) ofthe sNAG nanofibers are
between about 2 to about 10 microns, about 3 to about 8 microns, about 4 to about 7 microns,
about 4 to about 10 microns, or about 5 to about 10 microns in length as measured by any
method known to one skilled in the art, for example, by SEM. In another specific embodiment,
all (100%) of the sNAG nanofibers are between about 2 to about 10 microns, about 3 to about 8
microns, about 4 to about 7 microns, about 4 to about 10 microns, or about 5 to about 10 microns
in length as measured by any method known to one d in the art, for example, by SEM.
‘In certain embodiments, the sNAG nanofibers fibers are in a range between 0.005 to 5
microns in thickness and/0r diameter as deterr'nined by electron microscopy. In specific
embodiments, the sNAG nanofibers are about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09,
0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3,
1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.2, 2.4, 2.6, 2.8, 3 or 4 microns in thickness and/or diameter on
e, or any range in between (e.g., 0.02 to 2 microns, 0.02 to 1 microns, 0.02 to 0.75
microns, 0.02 to 0.5 microns, 0.02 to 0.5 microns, 0.05 to 1 microns, 0.05hto 0.75 microns, 0.05
to 0.5 microns, 0.1 to 1 microns, 0.1 to 0.75 microns, 0.1 to 0.5 s, etc.). In c.
embodiments, the majority (and in n embodiments, at least 60%, 70%, 80%, 90%, 95%,
98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to 75%, 65% to 75%,
75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) of the sNAG nanofibers
have a thickness or diameter of about 0.02 to 1 microns. In other specific embodiments, the
majority (and in n embodiments, at least 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%,
99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to 75%, 65% to 75%, 75% to 85%, 75%
to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) of the sNAG nanofibers have a thickness or
diameter of about 0.05 to 0.5 microns. In specific embodiments, all (100%) of the sNAG
nanofibers have a thickness or diameter of about 0.02 to 1 microns or about 0.05 to 0.5 microns.
In certain embodiments, the majority (and in n embodiments, at least 60%, 70%, 80%,
90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to 75%,
65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) ofthe sNAG
nanofibers have a thickness or diameter of about 0.02 to 2 microns, 0.02 to 1 s, 0.02 to
0.75 microns, 0.02 to 0.5 microns, 0.02 to 0.5 microns, 0.05 to 1 microns, 0.05 to 0.75 s,
0.05 to 0.5 microns, 0.1 to 1 microns, 0.1 to 0.75 microns, or 0.1 to 0.5 microns.
In certain ments, the majority (and in certain embodiments, at least 60%, 70%,
80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to
75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) of the
sNAG nanofibers are between 1 and 15 microns, or between (or in the range of) l to 10 s,
2 to 10 microns, 3 to 10 microns, 4 to 10 microns, 4 to 7 microns, 5 to 10 microns, or 5 to l5
microns in length and have a thickness or er of about 0.02 to 1 microns.
In certain embodiments, the molecular weight of the sNAG nanofibers is less than
100kDa, 90kDa, 80kDa, 75kDa, 70 kDa, 65 kDa, 60kDa, 55kDa, 50kDa, 45 kDA, 40kDa,
35kDa, 30kDa, or 25kDa. In certain embodiments, the majority (and in certain ments, at
least 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55%
to 65%, 55% to 75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95%
to 99%) ofthe sNAG nanofibers have a molecular weight of less than 100kDa, 90kDa, 80kDa,
75kDa, 70 kDa, 65 kDa, 60kDa, 55kDa, 50kDa, 45 kDA, 40kDa, 35kDa, 30kDa, or 25kDa. In
other embodiments, the majority (and in certain embodiments, at least 60%, 70%, 80%, 90%,
95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to 75%, 65% to
75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to 99%) ofthe sNAG
nanofibers have a molecular weight between about 5kDa to 100kDa, about lOkDa to 100kDa,
about 20kDa to 100kDa, about IOkDa to 80kDa, about 20kDa to 80kDa, 20kDa to 75kDa, about
25kDa to about 75kDa, about 30kDa to about 80kDa, about 30kDa to about 75kDa, about 40kda
to about 80kDa, about 40kDa to about 75kDa, about 40kDa to about 70kDa, about 50kDa to
about 70kDa, or about 55kDa to about 65kDa. In one embodiment, the majority (and in certain
embodiments, at least 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%,
or between 55% to 65%, 55% to 75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%,
90% to 95%, or 95% to 99%) of the sNAG nanofibers have a molecular weight of about 60kDa.
In certain embodiments, 1% to 5%, 5% to 10%, 5% to 15%, 20% to 30% or 25% to
% of the sNAG nanofibers are deacetylated. In some embodiments, 1%, 5%, 10%, 15%, 20%,
%, or 30% of the sNAG nanofibers are deacetylated. In other embodiments, less than 30%,
%, 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1% of the sNAG nanofibers are deacetylated. In
some embodiments, equal to or more than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99%, or all (100%), of the
sNAG nanofibers are deacetylated. In other embodiments, less than 1%, 5%, 10%, 15%, 20%,
%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or
100% of the sNAG nanofibers are deacetylated.
In certain embodiments, 70% to 80%, 75% to 80%, 75% to 85%, 85% to 95%, 90%
to 95%, 90% to 99% or 95% to 100% of G nanofibers are acetylated. In some
embodiments, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or 100% ofthe sNAG nanofibers
are acetylated. In other embodiments, more than 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%,
99%, 99.5% or 99.9% of the sNAG nanofibers are acetylated. In some embodiments, equal to or
more than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, 95%, 97%, 98% or 99%, or all (100%), ofthe sNAG nanofibers are
acetylated. In other embodiments, less than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% ofthe
sNAG nanofibers are acetylated.
In some embodiments, the majority (and in certain embodiments, at least 60%, 70%,
80%, 90%, 95%, 98%, 99%, 99.5%, 99.9%, or 100%) of the sNAG ers are between (or in
the range of) 2 to 12 microns, 2 to 10 microns, 4 to 15 microns, 4 to 10 microns, 5 to 15 s,
or 5 to 10 microns, and such sNAG nanofibers are at least 70%, 75%, 80%, 85%, 90%, 95%,
97%, 98%, 99% or 100% acetylated.
In some ments, the sNAG nanofibers comprise at least one glucosamine
ccharide, and may r comprise at least 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, 95% or 99% of the N-acetylglucosamine monosaccharides. In other embodiments,
2012/033782
the sNAG bers comprise at least one N-acetylglucosamine monosaccharide, and may
further comprise at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% of
glucosamine ccharides.
In one aspect, the sNAG nanofibers increase the metabolic rate of serum-starved
human umbilical cord vein endothelial cells (“EC”) in a MTT assay. A MTT assay is a
laboratory test and a standard colorimetric assay (an assay which measures changes in color) for
measuring cellular eration (cell growth). Briefly, yellow MTT (3-(4,5-Dimethylthiazol
yl)-2,5-diphenyltetrazolium bromide, a tetrazole) is reduced to purple forrnazan in the
mitochondria of living cells. This reduction takes place only when mitochondrial reductase
enzymes are active, and therefore conversion can be directly related to the number of viable
(living) cells. The MTT assay is described in Example 6, infra, where it is utilized to assess the
effect of sNAG nanofibers on the metabolic rate of EC cells. The metabolic rate of cells may
also be ined by other ques commonly known to the skilled artisan.
In another aspect, the sNAG nanofibers do not rescue apoptosis of serum-starved EC
in a trypan blue exclusion test. A trypan blue exclusion test is a dye exclusion test used to
determine the number of viable cells present in a cell suspension. It is based on the ple that
live cells possess intact cell membranes that exclude certain dyes, such as trypan blue, Eosin, or
propidium, whereas dead cells do not. The trypan blue assay is described in Example 6, infra,
where it is utilized to assess the effect of sNAG nanofibers on cell viability of EC cells. The
viability of cells may also be ined by other ques commonly known to the skilled
artisan.
In certain embodiments, compositions comprising the sNAG nanofibers are
described, wherein the sNAG ers increase the metabolic rate of serum—starved human
umbilical cord vein endothelial cells in a MTT assay and/or do not rescue apoptosis of serum-
starved human umbilical cord vein endothelial cells in a trypan blue exclusion test. In some
ments, the sNAG nanofibers increase the metabolic rate of serum-starved human
umbilical cord vein endothelial cells in a MTT assay and do not rescue apoptosis of serum—
starved human umbilical cord vein endothelial cells in a trypan blue exclusion test.
In a specific embodiment, the sNAG nanofibers are biocompatible. Biocompatibility
may be determined by a variety of techniques, including, but not limited to such procedures as
the elution test, intramuscular tation, or intracutaneous or ic injection into animal
subjects. Such tests are described in US. Patent No. 342 (see, e.g., Example 10), which is
incorporated by reference herein in its ty. Some of the biocompatibility tests are described
in Example 7, infra, which show that sNAG nanofibers are non—reactive in such tests.
In certain embodiments, the sNAG nanofibers used in the methods described herein
are non-reactive in a biocompatibility test or tests. For example, the sNAG nanofibers used in
the methods described herein may be non-reactive when tested in an elution test, an
uscular implantation test, an intracutaneous test, and/or a systemic test. In other
embodiments, the sNAG nanofibers used in the methods described herein have Grade 0 or Grade
1 test score when tested in an elution test, an intramuscular implantation test, an intracutaneous
test, or a systemic test. In yet another embodiment, the sNAG nanofibers used in the methods
described herein are at most mildly reactive when tested in an elution test, an intramuscular
implantation test, an intracutaneous test, and/or a systemic test. In certain embodiments, the
compositions described herein do not cause an allergenic reaction or an irritation. In other
embodiments, the itions described herein cause at most a mild allergenic reaction or a
mild irritation, e.g., at the site of application. The relevant tests and evaluation of test results are
described in, e.g., US. Patent No. 6,686,342, which is orated herein by reference in its
entirety, and in Section 6.8, infra. K
In a specific embodiment, the sNAG nanofibers are non-reactive when tested in an
uscular implantation test. In one , an intramuscular tation test is an
uscular implantation test — ISO 4 weekimplantation, as described in Section 6.8.3, infra.
In certain embodiments, the sNAG ers display no biological reactivity as determined by
an elution test (Elution Test Grade = O). In some embodiments, the sNAG ers have a test
score equal to “O” and/or are at most a negligible irritant as determined by intracutaneous
injection test. In some embodiments, the sNAG nanofibers elicit no ermal reaction (i.e.,
Grade I reaction) in Kligman test and/or have a weak allergenic potential as determined by
Kligman test. e 7, infra, shows that sNAG nanofibers are non—reactive in an
intramuscular implantation test, an intracutaneous injection test, and Kligman test.
In certain aspects, the sNAG nanofibers are immunoneutral (i.e., they do not elicit an
immune response).
In some embodiments, the sNAG nanofibers are biodegradable. The sNAG
nanofibers preferably degrade within about 1 day, 2 days, 3 days, 5 days, 7 days (1 week), 8
days, 10 days, 12 days, 14 days (2 weeks), 17 days, 21 days (3 weeks), 25 days, 28 days (4
weeks), 30 days, 1 month, 35 days, 40 days, 45 days, 50 days, 55 days, 60 days, 2 months, 65
days, 70 days, 75 days, 80 days, 85 days, 90 days, 3 months, 95 days, 100 days or 4 months after
administration or implantation into a t.
In certain embodiments, the sNAG nanofibers do not cause a detectable foreign body
reaction. A n body on, which may occur during wound healing, includes
accumulation of exudate at the site of injury, infiltration of inflammatory cells to debride the
area, and the formation of granulation tissue. The persistent presence of a foreign body can
inhibit full healing. Rather than the resorption and reconstruction that occurs in wound healing,
the foreign body reaction is characterized by the formation of foreign body giant cells,
encapsulation of the foreign object, and chronic inflammation. Encapsulation refers to the firm,
generally avascular collagen shell deposited around a foreign body, effectively isolating it from
the host tissues. In one embodiment, treatment ofa site (e.g., a wound or a site ofa bacterial
infection in a wound) with the sNAG nanofibers does not elicit a detectable foreign body
reaction in 1' day, 3 days, 5 days, 7 days, 10 days or 14 days after treatment. In one such
embodiment, ent of a site (e.g., a wound) with the sNAG nanofibers-does not elicit a
foreign body encapsulations in 1 day, 3 days, 5 days, 7 days, 10 days or 14 days after treatment.
In some ments, the sNAG nanofibers (i) comprise fibers, wherein majority of
the fibers are between about 1 and 15 microns in length, and (ii) (a) se the metabolic rate
of serum-starved EC in a MTT assay and/or do not rescue apoptosis of serum-starved EC in a
trypan blue exclusion test, and (b) are active when tested in an intramuscular implantation
test. In certain embodiments, the sNAG nanofibers (i) comprise fibers, wherein ty of the
fibers are between about 1 and 12 microns in length, and (ii) (a) increase the metabolic rate of
serum-starved EC in a MTT assay and/or do not rescue apoptosis of serum—starved EC in a
trypan blue exclusion test, and (b) are non-reactive when tested in an intramuscular implantation
test. In some embodiments, the sNAG ers (i) comprise fibers, n majority of the
fibers are between (or in the range of) l to 10 microns, 2 to 10 s, 4 to 10 microns, 5 to 10
microns, or 5 to 15 microns in length, and (ii) (a) se the metabolic rate of serum-starved
EC in 3 MTT assay and/or do not rescue apoptosis of serum-starved EC in a trypan blue
exclusion test, and (b) are non—reactive when tested in an intramuscular implantation test. In
some embodiments, the sNAG ers (i) comprise fibers, wherein majority of the fibers are
between about 4 and 10 microns in length, and (ii) (a) increase the metabolic rate of serum-
starved EC in a MTT assay and/or do not rescue apoptosis of serum-starved EC in a trypan blue
exclusion test, and (b) are non-reactive when tested in an intramuscular implantation test. In
certain embodiments, the sNAG nanofibers (i) se fibers, wherein majority of the fibers are
between about 4 and 7 microns in length, and (ii) (a) increase the metabolic rate of serum—starved
EC in a MTT assay and/or do not rescue apoptosis of serum-starved EC in a trypan blue
exclusion test, and (b) are non-reactive when tested in an intramuscular implantation test.
In certain embodiments, the sNAG nanofibers do not have a direct effect on the
growth or survival of bacteria, such as S. aureus, as determined by one d in the art. In other
embodiments, sNAG nanofibers do not have a direct effect on the growth or survival of bacteria,
such as S. aureus, as determined by the methods set forth in Section 6.2.2.5, infra. In some
embodiments, the sNAG 'nanofibers do not have a direct effect in vitro on bacterial growth or
al. In one embodiment, the sNAG nanofibers do not have a direct effect (e.g., in vitro) on
growth or al of gram—negative bacteria. In another embodiment, the sNAG nanofibers do
not have a direct effect (e.g., in vitro) on growth or survival of ositive bacteria. In yet
another embodiment, the sNAG nanofibers do not have a direct effect (e.g., in vitro) on growth
or survival of either gram-positive or gram-negative bacteria.
In some embodiments, the sNAG nanofibers (i) se fibers, wherein majority of
the fibers are between (or in the range of) about 1 and 15 s, l and 12 microns, l and 10
microns, 4 and 10 microns, 4 and 15 microns, 5 and 10 microns, 5 and 15 microns, or 4 and 7
s in length, (ii) do not have an effect on bacterial growth or survival of Staphylococcus
aureus bacterial cultures in vitro, and (iii) are non-reactive when tested in a biocompatibility test
(e.g., an intramuscular implantation test).
In certain embodiments, the sNAG nanofibers induce a certain pattern of gene
expression (RNA or protein expression as determined by, e.g., RT-PCR, microarray or ELISA)
in a cell, tissue or organ treated with or exposed to a sNAG nanofiber composition. Specifically,
in some ments, the sNAG ers or a composition comprising the sNAG nanofibers
induce sion of one or more defensin proteins, one or more defensin-like proteins, and/or
one or more ike receptors. In yet other embodiments, the sNAG nanofibers or a
composition comprising the sNAG nanofibers induce expression of one or more ns that are
known to have an anti-bacterial effect.
In certain embodiments, the sNAG nanofibers or a composition comprising the sNAG
nanofibers induce expression of one or more a-defensins (e.g., DEFAl (i.e., u-defensin l),
, DEFA3, DEFA4, DEFAS, DEFA6), one or more B-defensins (e.g., DEFBl (i.e., B-
defensin 1), DEFBZ, DEFB4, DEFBIO3A, DEFBIO4A, SB, DEFB107B, DEFB108B,
DEFBl 10, DEFB112, 4, DEFB118, DEFB119, DEFB123, DEFBIZ4, DEFBIZS,
DEFB126, DEFB127, DEFBIZS, DEFBIZ9, DEFBl3l, DEFB136), and/or one or more 6-
ins (e.g., DEFTIP). In some embodiments, the sNAG nanofibers or a composition
comprising the sNAG nanofibers induce expression of one or more of DEFAI, DEFA3, DEFA4,
DEFAS, DEFBl, DEFB3, DEFBlO3A, DEFB104A, DEFB108B, DEFBl 12, DEFB114,
DEFB118, DEFB119, DEF13123, DEFBI24, DEFB125, DEFB126, DEFB128, DEFBIZ9 and
DEFB131. In n embodiments, the sNAG nanofibers or a composition comprising the
sNAG nanofibers induce expression of one or more Toll receptors (e.g., TLRl, TLR2, TLR3,
TLR4, TLRS, TLR6, TLR7, TLR8, TLR9, TLRIO, TLRl 1, and/or TLR12). In other
embodiments, the sNAG ers or a composition comprising the sNAG nanofibers induce
expression of one or more of IL-1, CEACAM3, SPAGI l, SIGIRR (ILl-like receptor), IRAKI,
IRAKZ, IRAK4, TBKI, TRAF6 and IKKi. In some embodiments, the sNAG nanofibers or a
composition comprising the sNAG ers induce expression of one or more of IRAKZ,
SIGIRR, TLRl, TLR2, TLR4, TLR7, TLRS, TLRIO and TRAF6. In one embodiment, the
sNAG nanofibers or a composition sing the sNAG nanofibers induce expression of at
least one of the above—listed gene products.
In some embodiments, the sNAG nanofibers or a ition comprising the sNAG
nanofibers induce sion of one or more of the above-listed genes in the amount equal to or
more than about 0.25 fold, 0.5 fold, 1 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5
fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 12 fold, 15 fold or 20 fold as compared to the
level of expression ofthe one or more ofthe above-listed genes in a cell, tissue or organ ofa
t before treatment with the sNAG nanofibers (e.g., a known average level of expression of
the one or more of the above-listed genes). In some embbdiments, the sNAG nanofibers or a
composition comprising the sNAG nanofibers induce expression of one or more of the above-
listed genes in the amount equal to or more than about 10%, 25%, 50%, 75%, 100%, 125%,
150%, 175%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 550%, 600%,
650%, 700%, 750%, 800%, 900% or 1000% the level of expression of the one or more ofthe
above-listed genes in a cell, tissue or organ of a subject before treatment with the sNAG
nanofibers (e.g., a known average level of expression of the one or more of the above-listed
genes).
In some ments, the sNAG nanofibers but not long poly-N—acetylglucosamine,
chitin and/or chitosan induce expression of the one or more genes listed above, as determined by
a method known to one skilled in the art, or described . In some of these embodiments,
long poly-N-acetylglucosamine, chitin and/or chitosan do not induce expression of the one or
more genes listed above or induce lower level (e.g., more than 1.25 fold, 1.5 fold, 2 fold, 2.5
fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold lower) of
expression of the one or more genes listed above as compared to the level of expression of the
one or more genes listed above induced by the sNAG nanofibers, as determined by a method
known to one skilled in the art, or described herein.
In certain ments, the sNAG nanofibers or a composition comprising the sNAG
ers induce a gene expression profile that is consistent with, similar to, about the same as,
or equivalent to one or more gene expression profiles demonstrated in Tables I, II, III, V, VIII
and IX, Sections 6.2-6.5, infra. In some embodiments, the sNAG nanofibers or a ition
sing the sNAG nanofibers induce expression of one or more of the genes shown to be
lated by sNAG treatment in Tables I, II, III, V, VIII and IX, Sections 6.2-6.5, infra. In
some embodiments, the sNAG nanofibers or a composition comprising the sNAG nanofibers
induce expression of the majority or all of the genes shown to be upregulated by sNAG treatment
in Tables I, II, 111, V, VIII and IX, Sections 6.2-6.5, infra. In some of these embodiments, gene
expression levels are measured at 1 hour, 2 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours,
12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 48 hours, 3 days or 5 days after
treatment of a cell, tissue or organ with a sNAG nanofiber composition by a method known to
one skilled in the art, or described herein.
In certain embodiments, the sNAG nanofibers or a composition comprising the sNAG
nanofibers induce a gene expression profile that differs from the profile induced by long poly-N-
acetylglucosamine polymers or fibers. In specific embodiments, a gene expression profile
induced by the sNAG nanofibers is consistent with, similar to, about the same as, or lent
to that shown in Tables I, II, 111, V, VIII and IX, Sections 6.2-6.5, infra, whereas gene expression
profile induced by long -acetylglucosamine polymers or fibers is consistent with, similar
to, about the same with, or equivalent to that shown in Table VIII and/or IX, Section 6.5, infra.
In other embodiments, the sNAG nanofibers or a composition comprising the sNAG nanofibers
induce a gene expression profile that differs from the gene sion profile induced by chitin
or chitosan.
In a specific ment, the sNAG nanofibers are obtained by irradiating poly-N-
acetylglucosamine and/or a derivative thereof. See Section 5.1.1, infra, regarding poly-N-
acetylglucosamine and derivatives thereof and Section 5.2, infra, regarding methods for
producing the sNAG nanofibers using irradiation. Irradiation may be used to reduce the length
of -acetylglucosamine fibers and/or poly—N-acetylglucosamine derivative fibers to form
shortened poly-B-l——>4—N-acetylglucosamine fibers and/or ned poly-N-acetylglucosamine
derivative fibers, i.e. sNAG nanofibers. Specifically, irradiation may be used to reduce the
length and lar weight of poly-N-acetylglucosamine or a derivative thereof t
disturbing its microstructure. The infrared spectrum (IR) of sNAG nanofibers is similar to, about
the same as, or equivalent to that of the non-irradiated poly-B-l—r4—N-acetylgulcosamine or a
derivative f.
In one embodiment, the sNAG nanofibers are not derived from chitin or chitosan.
Whereas in another embodiment, the compositions described herein may be derived from chitin
or chitosan, or the sNAG nanofibers may be derived from chitin or chitosan.
.1.1 Poly-N-Acetylglucosamine and tives Thereof
US. Patent Nos. 5,622,834; 5,623,064; 5,624,679; 5,686,115; 5,858,350; 6,599,720;
6,686,342; 7,115,588 and US. Patent Pub. 2009/0117175 (each of which is incorporated herein
by reference) describe the poly-N—acetylglucosamine and derivatives thereof, and methods of
producing the same. In some embodiments, the poly-N-acetylglucosamine has a [Ll->4
configuration. In other embodiments, the poly-N-acetylglucosamine has a a-1—>4 configuration.
The poly-N-acetylglucosamine and derivatives thereof may be in the form of a polymer or in the
form of a fiber.
Poly-N-acetylglucosamine can, for example, be produced by, and may be purified
from, microalgae, preferably diatoms. The diatoms which may be used as starting sources for
the tion of the poly-N-acetylglucosamine include, but are not d to members of the
Coscinodiscus genus, the ella genus, and the siosira genus. Poly-N-
acetylglucosamine may be obtained from diatom cultures via a number of different methods,
including the mechanical force method and chemical/biological method known in the art (see,
e.g., US. Patent Nos. 834; 064; 5,624,679; 5,686,115; 5,858,350; 6,599,720;
6,686,342; and 7,115,588, each of which is incorporated herein by reference in its ty). In
certain embodiments, the poly-N-acetylglucosamine is not derived from one or more of the
following: a shell fish, a crustacean, an insect, a fungi or yeasts.
In one embodiment, poly-[i-l—)4-N-acetylglucosamine is d from a process
comprising a) treating a microalgae comprising a cell body and a poly-B-l——>4-N-
acetylglucosamine polymer fiber with a biological agent (such as hydrofluoric) capable of
separating the N-acetylglucosamine r fiber from the cell body for a sufficient time so that
the poly-B-l—»4-N-acetylglucosamine polymer fiber is released from the cell body; b)
ating the poly-B-1—>4—N—acetylglucosamine polymer fiber from the cell body; and c)
removing contaminants from the segregated poly-B-l—>4-N-acetylglucosamine polymer fiber, so
that the poly-B-l—>4-N-acetylglucosamine polymer is isolated and purified.
In other embodiments, the poly-B-l—»4-N-acetylglucosamine may be derived from
one or more of the following: a shell fish, a crustacean, an insect, a fungi or . In certain
embodiments, the compositions described herein do not comprise chitin or chitosan.
One or more of the monosaccharide units of the poly-N-acetylglucosamine may be
ylated. In certain embodiments, 1% to 5%, 5% to 10%, 5% to 15%, 20% to 30% or 25%
to 30% of the poly-N-acetylglucosarnine is deacetylated. In some embodiments, 1%, 5%,
%,15%, 20%, 25%, or 30% of the poly-N-acetylglucosamine is deacetylated. In other
embodiments, less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1% of the poly-N-
acetylglucosamine is deacetylated. In some embodiments, equal to or more than 1%, 5%, 10%,
%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,
95% or'99%, or all (100%), of the poly-N-acetylglucosamine is deacetylated. In other
embodiments, less than 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,
65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of the poly-N-acetylglucosamine is
deacetylated.
In certain embodiments, a poly-N-acetylglucosamine composition comprises 70% to
80%, 75% to 80%, 75% to 85%, 85% to 95%, 90% to 95%, 90% to 99% or 95% to 100% of
acetylated amine (i.e., N-acetylglucosamine) monosaccharides. In some embodiments, a
poly-Nacetylglucosamine composition comprises 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%,
99% or 100% of acetylated glucosamine (i.e., N-acetylglucosamine) monosaccharides. In other
embodiments, a poly-N-acetylglucosamine composition comprises more than 70%, 75%, 80%,
85%, 90%, 95%, 97%, 98%, 99%, 99.5% or 99.9% of the acetylated glucosamine. In some
embodiments, a poly-N—acetylglucosamine composition comprises equal to or more than 1%,
%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, 97%, 98%, or 99%, or all , of the acetylated amine. In other
embodiments, a poly-N-acetylglucosamine composition comprises less than 1%, 5%, 10%, 15%,
%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,
99%, or 100% of the ated glucosamine.
In some ments, a poly-N-acetylglucosamine composition ses at least
one glucosamine monosaccharide, and may further se at least 10%, 20%, 30%, 40%,
50%, 60%, 70%, 0%, 95% or 99% of N-acetylglucosamine monosaccharides. In other
embodiments, a poly-N-acetylglucosamine composition comprises at least one N—
acetylglucosamine monosaccharide, and may further comprise at least 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, 95% or 99% of glucosamine monosaccharides.
Derivatives of poly-N-acetylglucosamine may also be used in a composition
described herein. Derivatives of poly-N-acetylglucosamine and methods of making such
derivatives are described in U.S..Patent No. 5,623,064 (see, e.g., Section 5.4), which is
incorporated by reference herein in its entirety. Derivatives of poly-N-acetylglucosamine may
include, but are not limited to, partially or completely deacetylated poly-N—acetylglucosamine, or
its deacetylated tives. Further, poly-N-acetylglucosamine may be derivatized by being
sulfated, phosphorylated and/or nitrated. Poly-N-acetylglucosamine tives include, e.g.,
sulfated poly-N-acetylglucosamine derivatives, phosphorylated poly-N-acetylglucosamine
derivatives, or nitrated poly-N-acetylglucosamine derivatives. Additionally, one or more of the
monosaccharide units of the poly-N-acetylglucosamine may contain one or more sulfonyl groups
one or more O-acyl groups. In addition, one or more ofthe monosaccharides of the deacetylated
poly-N-acetylglucosamine may contain an N-acyl group. One .or more of the monosaccharides
of the poly-N-acetylglucosamine or of its deacetylated derivative, may contain an O-alkyl group.
One or more of the monosaccharide units of the poly -N-acetylglucosamine may be an alkali
derivative. One or more of the monosaccharide units of the deacetylated derivative of -
acetylglucosamine may contain an N-alkyl group. One or more of the monosaccharide units of
2012/033782
the deacetylated derivative of poly-N-acetylglucosamine may contain at least one alogen
derivative. One or more of the monosaccharide units ofthe deacetylated derivative of poly- N-
acetylglucosamine may form a salt. One or more of the monosaccharide units of the
deacetylated derivative of poly-N—acetylglucosamine may form a metal chelate. In a specific
embodiment, the metal is zinc. One or more of the monosaccharide units of the deacetylated
‘derivative of ~acetylglucosamine may contain an N-alkylidene or an N-arylidene group.
In one embodiment, the derivative is an acetate derivative. In another embodiment, the
derivative is not an acetate derivative. In one ment the poly-N-acetylglucosamine or
deacetylated -acetylglucosamine is derivatized with lactic acid. Wherein, in another
embodiment, the derivative is not derivatized with lactic acid.
.2 Methods of Producing sNAG Nanofibers
The -acetylglucosamine polymers or fibers, and any derivatives of poly-N-
acetylglucosamine polymers or fibers described above, can be irradiated as dry polymers or
fibers or r or fiber membranes. Alternatively, poly-N-acetylglucosamine polymers or
fibers, and any derivatives of poly-N-acetylglucosamine polymers or fibers described above, can
be irradiated when wet. The methods of making sNAG nanofibers by irradiation and the sNAG
nanofibers so produced have been described in US. Patent Pub. No. 2009/0117175, which is
incorporated by reference herein in its entirety.
In certain embodiments, the poly-N-acetylglucosamine rs or fibers are
formulated into a suspension/slurry or wet cake for irradiation. Irradiation can be performed
prior to, concurrently with or following the formulation of the polymers or fibers into its final
formulation, such as a dressing. Generally, the polymer or fiber content of suspensions/slurries
and wet cakes can vary, for e from about 0.5 mg to about 50 mg of r or fiber per 1
ml of distilled water are used for slurries and from about 50 mg to about 1000 mg of polymer or
fiber per 1 ml of distilled water are use for wet cake ations. The polymer or fiber may
first be lized, frozen in liquid nitrogen, and pulverized, to make it more susceptible to
forming a suspension/slurry or wet cake. Also, the suspensions/slurries can be filtered to remove
water such that a wet cake is formed. In certain aspects, the polymer or fiber is irradiated as a
suspension comprising about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10
mg, 12 mg, 15 mg, 18 mg, 20 mg, 25 mg or 50 mg ofpolymer or fiber per m1 of distilled water,
or any range in between the foregoing embodiments (e.g., 1—10 mg/ml, 5-15 mg/ml, 2—8 mg/ml,
WO 42581
-50 mg/ml, etc.). In other aspects, the polymer or fiber is irradiated as a wet cake, comprising
about 50-1,000 mg r or fiber per 1 ml of distilled water. In specific embodiments, the wet
cake comprises about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg of polymer or
fiber per 1 ml distilled water, or any range in between (e.g., 100-500 mg/ml, 300-600 mg/ml, 50-
1000 mg/ml, eta).
The irradiation is preferably in the form of gamma radiation, e-beam radiation, or x-
rays. Two sources of irradiation are preferred: radioactive nuclides and electricity. In specific
embodiment, the radioactive nuclides are cobalt-60 and cesium-137. Both of these nuclides emit
gamma rays, which are photons containing no mass. The gamma rays have energies from 0.66
to 1.3 MeV. Using electricity, electrons are generated and rated to energies up to 10 MeV
or higher. When irradiating polymers or fibers to reduce their size, a consideration to take into
t is that the depth of penetration of materials with densities similar to water by 10 MeV
electrons is limited to about 3.7 cm with one-sided exposure or about 8.6 cm with two-sided
exposure. Depth of penetration ses at lower electron energies. Electron energy can be
converted to x-rays by placing a metal (usually tungsten or tantalum) target in the electron beam
path. Conversion to x-rays is limited to electrons with energies up to 5 MeV. X-rays are photons
with no mass and can penetrate polymers or fibers similar to gamma rays. There is only about
8% efficiency in the conversion of electron energy to x—ray . High powered electron beam
'machines are needed in x—ray production facilities to account for the low conversion ncy.
In a c embodiment, the irradiation is gamma irradiation.
The absorbed dose of radiation is the energy absorbed per unit weight of product,
measured in gray (gy) or kilogray (kgy). For dried rs or fibers, the preferred absorbed
dose is about SOD-2,000 kgy of radiation, most ably about 750—1,250 kgy or about 900—
1,100 kgy of radiation. For wet polymers or fibers, the preferred absorbed dose is about 100-500
kgy of radiation, most preferably about 150-250 kgy or about 200—250 kgy of radiation.
] The dose of radiation can be described in terms of its effect on the length of the
polymers or fibers. In specific ments, the dose of radiation used preferably reduces the
length of the polymer or fiber by anywhere from about 10% to 90% of the starting length of the
polymer or fiber, respectively. In specific embodiments, the average length is reduced by about
%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%,
by about 80%, or by about 90%, or any range in between (e.g., 20-40%, 30-70%, and so on and
so forth). Alternatively, the dose of radiation used preferably reduces the length of the polymer
or fiber to anywhere from 1 to 100 microns. In specific embodiments, and ing on the
starting fiber length, the average length of the polymer or fiber is. reduced to less than about 15
microns, less than about 14 microns, less than about 13 microns, less than about 12 microns, less
than about 11 s, less than about 10 s, less than about 8 microns, less than about 7
microns, less than about 5 microns, less than about 4 microns, less than about 3 microns, less
than 2 microns, or less than 1 microns. In certain embodiments, the length of the majority (and in
certain embodiments, at least 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or
100%, or between 55% to 65%, 55% to 75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to
95%, 90% to 95%, or 95% to 99%) of the rs or fibers is reduced to no greater than about
microns, no greater than about 15 microns, no greater than about 12 microns, no greater than
about 10 microns, no greater than about 8 microns, no greater than about 7 microns, or no greater
than about 5 microns. In certain embodiments, irradiation of the polymers or fibers reduces the
- length of the majority (and in certain embodiments, at least 60%, 70%, 80%, 90%, 95%, 98%,
99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%, 55% to 75%, 65% to 75%, 75%
to 85%, 75% to 90%, 80% to 95%; 90% to 95%, or 95% to 99%) of the fibers to anywhere
between about 1 to 20 s, between about 1 to 15 microns, between about 2 to 15 microns,
between about 1 to 12 microns, between about 2 to 12 microns, between about 1 to 10 microns,
between about 2 to 10 microns, n about 1 to 8 microns, between about 2 to 8 microns,
between about 1 to 7 microns, between about 2 to 7 microns, between about 3 to 8 microns,
between about 4 to 10 microns, n about 4 to 7 microns, between about 5 to 10 microns,
between about 1 to 5 microns, between about 2 to 5 microns, between about 3 to 5 microns,
between about 4 to 10 microns, or any ranges between the ing lengths, which are also
assed.
The dose of radiation can also be described in terms of its effect on the molecular
weight of the polymer or fiber. In specific embodiments, the dose of radiation used preferably
reduces the molecular weight of the polymer or fiber by anywhere from, about 10% to 90% of the
starting weight of the polymer or fiber. In specific ments, the average molecular weight
is reduced by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about
60%, by about 70%, by about 80%, or by about 90%, or any range in n (e.g., 20-40%, 30-
70%, and so on and so forth). atively, the dose of radiation used preferably reduces the
molecular weight of the polymer or fiber to anywhere from 1,000 to 1,000,000 s. In
specific embodiments, and depending on the starting molecular weight, the average molecular
weight of the r or fiber is reduced to less than 1,000,000 daltons, less than 750,000
daltons, less than 500,000 daltons, less than 300,000 daltons, less than 200,000 daltons, less than
100,000 daltons, less than 90, 000 daltons, less than 80,000 daltons, less than 70,000 daltons, less
than 60,000 s, less than 50,000 daltons, less than 25,000 daltons, less than 10,000 daltons,
or less than 5,000 daltons. In certain embodiments, the average molecular weight is reduced to
no less than 500 s, no less than 1,000 daltons, no less than 2,000 daltons, no less 3,500
daltons, no less than 5,000 s, no less than 7,500 daltons, no less than 10,000 daltons, no
less than 25,000 daltons, no less than 50,000 daltons, no less than 60, 000 daltons or no less than
100,000 daltons. Any ranges between the foregoing average molecular weights are also
encompassed; for example, in certain ments, irradiation of the polymer or fiber reduces
the average molecular weight to anywhere between 10,000 to 100,000 daltons, between 1,000
and 25,000 daltons, between 50,000 and 500,000 daltons, between 25,000 and 100,000 daltons,
between 30,000 and 90,000 daltons, between about 40,000 and 80,000 daltons, n about
,000 and 75,000 daltons, between about 50,000 and 70,000 daltons, or n about 55,000
and 65,000 daltons and so on and so forth. In certain embodiments, irradiation of the polymers
or fibers reduces the molecular weight of the majority and in certain embodiments, at least 60%,
70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between 55% to 65%,
55% to 75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or 95% to
99%) of the fibers to anywhere between about 20,000 and 100,000 daltons, about 25,000 and
75,000 daltons, about 30,000 and 90,000 daltons, about 40,000 and 80,000 daltons, about 50,000
and 70,000 daltons, or about 55,000 and 65,000 daltons. In certain embodiments, irradiation of
the polymers or fibers reduces the lar weight of the majority and in n embodiments,
at least 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%, or between
55% to 65%, 55% to 75%, 65% to 75%, 75% to 85%, 75% to 90%, 80% to 95%, 90% to 95%, or
95% to 99%) of the fibers to about 60,000 daltons.
Following irradiation, slurries can be filtered and dried, and wet cakes can be dried, to
form compositions (e.g., dressings and other itions described herein) that are useful in the
practice of the invention.
2012/033782
.3 Compositions Comprising sNAG Nanofibers
The sNAG bers may be formulated in a variety of compositions for topical
administration as described herein.
] A composition comprising the sNAG nanofibers may be formulated as a cream, a
membrane, a film, a liquid solution, a suspension (e. g., a thick suspension), a powder, a paste, an
ointment, a itory, a gelatinious composition, an aerosol, a gel, or a spray. In one
embodiment, a composition comprising the sNAG nanofibers is formulated as an ultra—thin
membrane. In some embodiments, a composition comprising the sNAG nanofibers is formulated
as a dressing, a mat, or a bandage. In particular embodiments, compositions comprising sNAG
nanofibers are not solid or barrier-forming. Solid formulations suitable for solution in, or
suspension in, liquids prior to stration are also contemplated. It is also possible that such
compositions are orated in or coated on implantable devices, such as orthopedic implants
(for hip, knee, shoulder; pins, screws, etc), cardiovascular implants (stents, catheters, etc.) and
the like where the antibacterial activity would be of benefit.
] A composition comprising the sNAG nanofibers may include one or more of
pharmaceutically acceptable excipients. Suitable excipients may include water, saline, salt
solution, dextrose, glycerol, ethanol and the like, or combinations thereof. Suitable excipients
also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium
stearate, glycerol earate, oil (including those of petroleum, animal, vegetable or synthetic
, such as peanut oil, soybean oil, l oil, sesame oil and the like), talc, sodium
chloride, dried skim milk, propylene, glycol and the like. In addition, a ition comprising
‘ the sNAG nanofibers may include. one or more of g agents, emulsifying agents, pH
' buffering agents, and other agents. The sNAG nanofiber compositions may also be incorporated
in a physiologically acceptable carrier, for example in a physiologically acceptable carrier
suitable for topical application. The term “pharmaceutically acceptable” means approved by a
regulatory agency of the Federal or a state government or listed in the US. Pharmacopeia or
other generally recognized phannacopeia for use in animals, and more particularly in humans.
Examples of le ceutical carriers are described in "Remington's Pharmaceutical
Sciences" by E.W. Martin.
The final amount ofthe sNAG nanofibers in a composition may vary. For example,
the amount of the sNAG nanofibers in a composition (e.g., prepared for administration to a
2012/033782
patient) may be r than or equal to about 50%, about 60%, about 70%, about 75%, about
80%, about 85%, about 90%, about 95%, about 98%, or about 99% weight by volume. In one
embodiment, the amount of the sNAG nanofibers in a composition is about 95%, about 98%,
about 99, or about 100%. Also, the amount of the sNAG nanofibers in a composition (e.g.,
prepared for administration to a patient) may be about 50%-100%, about 60%-100%, about 70%—
100%, about 75%-100%, about 80%-100%, about 90%—100%, about 95%-100%, about 70%—
95%, about 75%-95%, about 80%-95%, about %, about 70%-90%, about 75%-90%, or
about 80%-90% weight/volume. A composition may comprise more than 30%, 40%, 50%, 60%,
70%, 75%, 80%, 90%, 95% or 99% solution of the sNAG nanofibers.
A sNAG nanofiber composition may be formulated into a wound dressing. In n
embodiments, a sNAG nanofiber composition is formulated as a wound dressing in the form of a
barrier, a ne, or a film. Alternatively, a sNAG nanofiber composition may be added to
dressing backings, such as barriers, membranes, or films. A barrier, ne, or film can be
supplied in a y of standard sizes, which can be further out and sized to the area being
treated. The backing can be a conventional dressing material, such as a bandage or gauze to
which a polymer or fiber is added or coated on, prior to application to the patient. Alternatively,
the sNAG nanofibers can be formulated as a r, membrane, or film made out of strings,
microbeads, pheres, or brils, or the composition can be formulated as a barrier—
forming mat. In certain embodiments, at least 75%, at least 85%, at least 90%, or at least 95% of
a dressing is composed ofthe sNAG nanofibers. In certain aspects, a dressing does not contain
a conventional dressing material such as a gauze or bandage. In such embodiments, the sNAG
nanofiber itself is ated as a wound dressing.
A composition comprising the sNAG nanofibers may further comprise any suitable
natural or synthetic polymers or fibers. Examples of suitable polymers or fibers include
cellulose polymers, n, polyaramides, polyamides, polyimides, polyamide/imides,
polyamidehydrazides, polyhydrazides, polyimidazoles, polybenzoxazoles, polyester/amide,
polyester/imide, polycarbonate/amides, polycarbonate/imides, polysulfone/amides, polysulfone
, and the like, copolymers and blends thereof. Other suitable classes of polymers or fibers
e polyvinyledene fluorides and polyacrylonitriles. Examples of these polymers or fibers
include those described in US. Patent Nos. RE 30,351; 4,705,540, 4,717,393; 4,717,394;
4,912,197; 4,838,900; 490; 4,851,505; 4,880,442; 4,863,496; 4,961,539; and European
Patent Application 0 219 878, all of which are incorporated by reference. The polymers or fibers
can include at least one of either of cellulose polymers, polyamides, polyaramides,
polyamide/imides or polyimides. In certain ments, the polymers or fibers include
polyaramides, polyester, urethan and trafluoroethylene. In one embodiment, the
compositions described herein comprise more than one type ofpolymer (e.g., the sNAG
er and cellulose).
In certain aspects, the sNAG nanofiber is the only active ingredient in a composition.
In other embodiments, a composition comprises one or more additional active
ingredients, e.g., an anti-viral agent, an ungal agent, an anti-yeast agent, a chemotherapeutic
agent or any other agent. In some embodiments, the additional active ingredient is one or more
of an anti-viral agent, an anti-fungal agent, an anti-yeast agent, a defensin peptide, a defensin-
like peptide, or a Toll—receptor-like peptide), or a grth factor. In specific embodiments, the
additional active ingredient is a growth factor such as one or more of PDGF-AA, PDGF-AB,
PDGF-BB, PDGF-CC, PDGF-DD, FGF-l, FGF-Z, FGF-S, FGF-7, FGF-lO, EGF, TGF-a, (HB-
EGF), amphiregulin, ulin, betacellulin, neuregulins, epigen, VEGF-A, VEGF-B, VEGF-C,
VEGF-D, VEGF—E, placenta growth factor (PLGF), angiopoietin-l , angiopoietin-Z, IGF-I, IGF-
II, hepatocyte growth factor OIGF), and macrophage-stimulating protein (MSP). In other
ments, the additional active ingredient is an agent that boost the immune system, a pain
relief agent, or a fever relief agent.
[001 17] In certain ments, the additional active ingredient is an anti-viral agent. Any
anti-viral agents well-known to one of skill in the art may be used in a sNAG nanoflber
composition. Non-limiting es of anti-viral agents include ns, polypeptides,
peptides, fusion proteins dies, nucleic acid molecules, organic les, inorganic
molecules, and small molecules that inhibit and/or reduce the ment of a virus to its
receptor, the internalization of a virus into a cell, the replication of a virus, or release of virus
from a cell. In particular, anti-viral agents include, but are not limited to, nucleoside analogs
(e.g., zidovudine, acyclovir, gangcyclovir, vidarabine, idoxuridine, trifluridine, and ribavirin),
foscarnet, dine, peramivir, rimantadine, saquinavir, indinavir, ritonavir, alpha-interferons
and other interferons, AZT, zanamivir (Relenza®), and oseltamivir u®). Other anti-viral
agents include influenza virus vaccines, e.g., Fluarix® (GlaxoSmithKline), FluMist®
(Medlmmune Vaccines), Fluvirin® (Chiron Corporation), Flulaval® (GlaxoSmithKline),
Afluria® (CSL Biotherapies Inc.), Agriflu® (Novartis) or Fluzone® (Aventis Pasteur).
] In certain embodiments, the additional active ingredient is an anti-cancer agent. In a
specific embodiment, the anti-cancer agent is a chemotherapeutic agent. Any anti-cancer agents
known to one of skill in the art may be used in a sNAG nanofiber composition. Exemplary anti-
cancer agents include: acivicin; anthracyclin; anthramycin; azacitidine (Vidaza);
bisphosphonates (e.g., pamidronate (Aredria), sodium clondronate (Bonefos), zoledronic acid
(Zometa), alendronate (Fosamax), etidronate, ibandomate, cimadronate, risedromate, and
tiludromate); carboplatin; chlorarnbucil; cisplatin; cytarabine ); ubicin
hydrochloride; bine (Dacogen); demethylation agents, docetaxel; doxorubicin; EphAZ
inhibitors; etoposide; fazarabine; fluorouracil; gemcitabine; e deacetylase inhibitors
(HDACs); interleukin 11 (including recombinant interleukin II, or rILZ), interferon alpha;
interferon beta; interferon gamma; lenalidomide (Revlimid); anti-CD2 antibodies (e.g.,
siplizumab (Medlmmune Inc. ; International Publication No. W0 02/098370, which is
orated herein by reference in its entirety»; melphalan; methotrexate; cin;
oxaliplatin; paclitaxel; puromycin; riboprine; spiroplatin; tegafur; teniposide; vinblastine sulfate;
vincristine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
Other examples of onal active ingredients that may be used in a sNAG
nanofiber composition include, but are not limited to angiogenesis inhibitors; antisense
oligonucleotides; sis gene modulators; apoptosis regulators; BCR/ABL antagonists; beta
lactam derivatives; casein kinase inhibitors (ICOS); en agonists; estrogen antagonists;
glutathione inhibitors; HMG CoA reductase inhibitors; immunostimulant peptides; insulin-like
growth -1 receptor tor; eron agonists; erons; interleukins; lipophilic
platinum compounds; ysin inhibitors; matrix metalloproteinase inhibitors; mismatched
double ed RNA; nitric oxide modulators; oligonucleotides; platinum compounds; n
kinase C inhibitors, protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase
inhibitors; raf antagonists; signal uction inhibitors; signal transduction modulators;
ation inhibitors; tyrosine kinase inhibitors; and urokinase receptor antagonists.
In some embodiments, the additional active ingredient is an anti-angiogenic agent.
Non-limiting examples of anti-angiogenic agents include ns, polypeptides, peptides,
conjugates, antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs,
Fab fragments, F(ab)2 fragments, and antigen-binding fragments thereof) such as antibodies that
specifically bind to TNF-a, nucleic acid molecules (e.g., antisense molecules or triple s),
organic molecules, inorganic molecules, and small molecules that reduce or inhibit angiogenesis.
Other examples of anti-angiogenic agents can be found, e.g., in US. Publication No.
2005/0002934 A1 at paragraphs 277-282, which is incorporated by reference in its entirety. In
other embodiments, the onal active ingredient is not an anti-angiogenic agent.
In some embodiments, the additional active ingredient is an anti-inflammatory agent.
miting examples of anti-inflammatory agents include eroidal anti-inflammatory
drugs (NSAIDs) (e.g., celecoxib (CELEBREXTM), diclofenac (VOLTARENTM), etodolac
(LODINETM), fenoprofen (NALFONTM), indomethacin (INDOCINTM), ketoralac
(TORADOLTM), oxaprozin (DAYPROTM), nabumentone (RELAFENTM), ac
(CLINORILTM), tolrnentin (TOLECTINTM), xib TM), naproxen (ALEVETM,
NAPROSYNTM), ketoprofen (ACTRONTM) and nabumetone (RELAFENTM)), dal anti-
inflammatory drugs (e.g., glucocorticoids, dexamethasone (DECADRONTM), corticosteroids
(e.g., methylprednisolone (MEDROLTMD, cortisone, hydrocortisone, prednisone
(PREDNISONETM and DELTASONETM), and solone (PRELONETM and
PEDIAPREDTM», anticholinergics (e.g., atropine sulfate, atropine methylnitrate, and
ipratropiurn bromide (ATROVENTTM)), betaZ-agonists (e.g., abuterol (VENTOLINTM and
PROVENTILTM), bitolterol (TORNALATETM), levalbuterol (XOPONEXTM), metaproterenol
(ALUPENTIM), pirbuterol (MAXAIRTM), terbutlaine (BRETHAIRETM and BRETHINETM),
albuterol (PROVEN'I‘ILTM, REPETABSTM, and VOLMAXTM), forrnoterol (FORADIL
AEROLIZERTM), and salrneterol (SEREVENTTM and SEREVENT DISKUSTM», and
methylxanthines (e.g., theophylline (UNIPHYLTM, URTM, SLO-BIDTM, AND TEHO-
42W».
In n embodiments, the additional active ient is an alkylating agent, a
nitrosourea, an antimetabolite, an anthracyclin, a topoisomerase II inhibitor, or a mitotic
inhibitor. ting agents include, but are not limited to, busulfan, cisplatin, carboplatin,
cholormbucil, cyclophosphamide, ifosfamide, decarbazine, rethamine, mephalen, and
olomide. oureas include, but are not limited to carrnustine (BCNU) and lomustine
(CCNU). Antimetabolites include but are not limited to 5-fluorouracil,'capecitabine,
methotrexate, abine, cytarabine, and fludarabine. Anthracyclins include but are not
2012/033782
limited to daunorubicin, doxorubicin, epirubicin, idarubicin, and mitoxantrone. Topoisomerase
II inhibitors include, but are not limited to, topotecan, irinotecan, etopiside (VP-16), and
teniposide. Mitotic tors include, but are not limited to taxanes (paclitaxel, xel), and
the vinca alkaloids (vinblastine, vincristine, and vinorelbine).
A sNAG nanofiber composition may contain collagen, although in certain aspects a
sNAG nanofiber composition does not contain en.
In n embodiments, a sNAG nanofiber composition does not comprise any
additional therapy. In certain ments, a sNAG nanofiber ition does not comprise
any onal anti-viral agent, anti-cancer agent, anti-fungal agent, anti-yeast agent, anti-
atory agent, chemotherapeutic agent, anti-angiogenic agent, a defensin peptide, 3
defensin-like peptide, a Toll-receptor—like peptide, or a growth factor.
In some embodiments, the additional active ingredient is not an anti-bacterial agent
(e.g., an antibiotic, a defensin e, 3 defensin-like e, or a Toll-receptor-like peptide), or
a growth factor. In specific embodiments, the additional active ingredient is not a growth ,
such as PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, PDGF-DD, FGF-l, FGF-2, FGF-S, FGF-
7, , EGF, TGF-a, (HB-EGF), amphiregulin, epiregulin, betacellulin, neuregulins, epigen,
VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placenta growth factor (PLGF), angiopoietin-
1, angiopoietin-Z, IGF-I, IGF-II, hepatocyte growth factor (HGF), and macrophage-stimulating
protein (MSP). In certain embodiments, the additional active ingredient is not an agents that
boost the immune system, a pain relief agent, or a fever relief agent.
In certain embodiments, the additional active ingredient is not an antibiotic from
one of the following s of antibiotics: ides (e.g., erythromycin, azithromycin),
lycosides (e.g., amikacin, gentamicin, neomycin, streptomycin), cephalosporins (e.g.,
cefadroxil, cefaclor, cefotaxime, cefepime), fluoroquinolones (e.g., ciprofloxacin, levofloxacin),
penicillins (e.g., penicillin, ampicillin, amoxicillin), tetracyclines (e. g., tetracycline,
doxycycline), and carbapenems (e.g., meropenem, em). In some embodiments, the
additional active ingredient is not vancomycin, sulfa drug (e.g., co-trimoxazole/trimethoprim-
sulfamethoxazole), tetracycline (e.g., doxycycline, minocycline), clindamycin, oxazolidinones
(e.g., linezolid), daptomycin, teicoplanin, quinupristin/dalfopristin (synercid), tigecycline, allicin,
bacitracin, nitrofurantoin, hydrogen peroxide, novobiocin, netilmicin, methylglyoxal, bee
defensin-1, tobramycin, chlorhexidine digluconate, chlorhexidine ate, levofloxacin, zinc,
and/or silver.
In other aspects, a sNAG nanofiber composition does not comprise a significant
amount of protein material. In specific embodiments, the protein content of a sNAG nanofiber
composition is no greater than 0.1%, 0.5% or 1% by weight. In other embodiments, the protein
content of the ition is ctable by sie staining.
] In one embodiment, zinc is also included in a sNAG nanofiber composition. In
addition to its antimicrobial properties, zinc also plays a role in wound healing (see s et
al., 1999, Adv Wound Care 12:137-8). The zinc is preferably added in the form of a salt, such as
zinc oxide, zinc sulphate, zinc acetate or zinc gluconate.
.4 Prophylactic and Therapeutic Uses
In certain embodiments, the itions described herein can be used to prevent
and/or treat infections and/or diseases for which an increase in defensin production and/or
ion is beneficial. Such diseases may be the result of a defensin deficiency or may derive
benefit from increased presence of defensins.
In a specific embodiment, the compositions described herein are used to treat and/or
prevent a disease which is associated with no or low level of expression of one or more defensin
peptides; or a mutation/deletion/low gene copy number ) in a gene or genes encoding
one or more of defensin peptides. Exemplary defensin genes that may be mutated/deleted/have
low GCN/not expressed or whose sion may be low or altered include any of the known a-
defensins (e.g., DEFAl, DEFAlB, DEFA3, DEFA4, DEFAS, DEFA6), any of the known B-
defensins (e.g., DEFBI, DEFBZ, DEFB4, DEFB103A, DEFB104A, DEFB105B, DEFB107B,
DEFBIOSB, DEFBl 10, DEFB112, DEFB114, DEFB118, DEFB119, DEFB123, DEFB124,
S, DEFB126, DEFB127, DEFB128, DEFB129, 1, DEFB136), and any ofthe
known B-defensins (e.g., DEFTlP). In some embodiment, the compositions described herein are
used to treat or prevent a disease or ion which is associated with no, low, or altered level of
expression of or a mutation/deletion/low GCN of one or more of the above-listed genes. In a
specific embodiment, the itions described herein are used to treat or prevent a disease or
infection which is associated with no, low, or altered level of expression of or a
mutation/deletion/low GCN of one or more of DEFAl , DEFA3, DEFA4, DEFAS; DEFBl ,
DEFB3, DEFB103A, DEFB104A, DEFB108B, DEFBl 12, DEFBl 14, DEFB118, DEFBl 19,
DEFB123, DEFB124, DEFB125, DEFB126, DEFB128, DEFBIZ9 and DEFB131. In some
embodiments, the compositions described herein are used to treat or prevent a disease or
infection which is associated with no, low, or altered level of expression of or a
mutation/deletion/low GCN of one or more Toll receptors (e.g., TLRl, TLR2, TLR3, TLR4,
TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLRl 1, and/or TLR12). In yet other embodiments,
the compositions bed herein are used to treat or prevent a disease or infection which is
associated with no, low, or altered level of expression of or a mutation/deletion/low GCN of one
or more of IL-1, CEACAM3, SPAGl l, SIGIRR(IL1-like receptor), IRAKI , IRAKZ, IRAK4,
TBKl TRAF6 and HUG. In some embodiments, the compositions described herein are used to
treat or prevent a disease or infection which is associated with no, low, or d level of
expression of or a mutation/deletion/low GCN of one or more of IRAKZ, SIGIRR, TLRl , TLR2,
TLR4, TLR7, TLR8, TLRIO and TRAF6.
A low level of expression of a gene is a level that is lower (e.g., more than 1.25 fold,
1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10
fold lower) than the “normal” level of expression. An altered level of expression of a gene is a
level that differs (e.g., by more than 20%, 25%, 30%, 50%, 75%, 100%, 150%, 200%, 250%,
300%) from the “normal” level of expression. In certain embodiments, the expression of one or
more defensin genes (e.g., listed defensin genes) in a patient to be administered a
composition bed herein may be less than less than 90%, less than 75%, less than 60%, less
than 50%, less than 30% or less than 20% of the “normal” sion of one or more defensin
genes. Wherein the “normal” expression of one or more in genes is: (i) the average
expression level known to be found in subjects not displaying symptoms or not diagnosed with
the disease or infection to be treated; (ii) the e expression level ed in three, five, ten,
twenty, twenty-five, fifty or more subjects not displaying symptoms or not diagnosed with the
disease or infection to be treated; and/or (iii) the level of expression detected in a patient to be
administered a composition described herein before the onset of the disease or infection.
] In another specific embodiment, the compositions described herein are used to treat a
solid tumor . Without being bound by any mechanism of action, the ability of sNAG
nanofibers to induce alpha and beta defensins (e.g., beta-defensin 1) may contribute to the anti-
cancer activity of the sNAG ers. Human alpha and beta defensins (e.g., beta-defensin 1)
have been shown to have anti-cancer activity. Exemplary solid tumor cancers that can be treated
with the compositions described herein include, without limitation, bone and connective tissue
sarcomas, brain cancer, breast , ovarian cancer, kidney cancer, pancreatic cancer,
esophageal cancer, stomach cancer, ovarian cancer, lung cancer (e.g., small cell lung cancer
(SCLC), non-small cell lung cancer (NSCLC), throat cancer, and mesothelioma), liver cancer,
and te cancer. In some embodiments, the compositions described herein are used to treat a
cancer caused by or associated with a viral infection. In a specific embodiment, the
compositions bed herein are used to treat Kaposi’s sarcoma. In certain embodiments,
treatment of a subject having a solid tumor by stration of a composition described herein
results in one or more of the following: reduction in the size of the solid tumor; prevention of
the metastasis of the solid tumor; prevention of the recurrence of the solid tumor; reduction in the
duration and/or severity of one or more symptoms associated with the solid tumor; reduction in
the number of ms associated with the solid tumor; prevention of the increase in the size of
the solid tumor; reduction/inhibition of proliferation of cancer cells of the solid tumor; reduction
in organ failure associated with the solid tumor; reduction of the incidence of hospitalization of
the subject; reduction of the hospitalization length of the subject; an increase the survival of the
subject; and/or ement or improvement of the lactic or therapeutic (s) of
r therapy in the subject.
In another specific ment, the compositions described herein are used to treat
skin cancer. Exemplary skin cancers that can be treated with the compositions described herein
include, without limitation, melanoma, basal cell carcinoma, and squamous cell carcinoma. In
certain embodiments, ent of a subject having a skin cancer by administration of a
composition described herein results in one or more of the following: reduction in the size of the
skin cancer; prevention of the metastasis of the skin cancer; prevention of the recurrence of the
skin cancer; reduction in the duration and/or severity of one or more symptoms ated with
the skin cancer; reduction in the number of symptoms associated with the skin cancer; reduction
in organ failure associated with the skin cancer; reduction of the incidence of hospitalization of
the subject; reduction of the hospitalization length of the subject; an increase the survival of the
subject; and/or enhancement or improvement of the prophylactic or therapeutic effect(s) of
another y in the t.
] In another specific embodiment, the compositions described herein are used to treat
inflammatory bowel disease (IBD). Without being bound by any mechanism of action, the
ability of sNAG nanofibers to induce alpha and beta defensins may contribute to the anti-IBD
activity of the sNAG nanofibers. Alpha and beta ins have been shown to have anti-IBD
activity. IBD includes, but is not limited to, Crohn’s disease and tive colitis. In n
embodiments, treatment of a subject having IBD by administration of a composition described
herein results in one or more of the following: prevention of the recurrence of IBD; reduction in
the duration and/or severity of one or more symptoms associated with IBD; reduction in the
number of symptoms associated with the IBD; reduction of the incidence of hospitalization of
the subject; reduction of the hospitalization length of the subject; and/or enhancement or
improvement of the prophylactic or therapeutic effect(s) of another therapy in the subject. Some
of the symptoms of IBD include abdominal pain, vomiting, diarrhea, rectal ng, severe
internal cramps/muscle spasms in the region of the pelvis, weight loss and various associated
complaints or diseases like arthritis, pyoderma gangrenosum, and/or primary sclerosing
cholangitis. In some embodiments, the compositions described herein prevent the onset or
development of one or more of the above-listed symptoms or other symptoms known in the art,
or reduce on and/or severity of one or more of these symptoms. In one embodiment, the
compositions described herein are used to treat tive colitis. Symptoms of ulcerative colitis
may include above listed symptoms of IBD, and may also include defecation often mucus-like
and with blood, tenesmus, and/or fever. e 9, infra, shows that sNAG ers are
effective to treat IBD based on the data obtained in an animal model of IBD. A composition
comprising sNAG nanofibers that can be used to treat IBD can be any sNAG composition
described herein. In one embodiment, a composition comprising sNAG nanofibers that can be
used to treat IBD is the same or similar to the composition bed in e 9.
In a specific embodiment, the compositions described herein are used to treat Crohn's
disease (e.g., ileal Crohn’s disease). Without being bound by any mechanism of , the
y of sNAG nanofibers to induce alpha and beta defensins may contribute to the anti-Crohn's
disease activity of the sNAG bers. Alpha and beta defensins have been shown to have
anti-Crohn's disease activity. In certain embodiments, treatment of a subject having Crohn’s
disease by administration of a composition described herein results in one or more of the
following: prevention of the recurrence of the s disease; reduction in the duration and/or
severity of one or more symptoms ated with the Crohn’s disease; reduction in the number
of symptoms associated with the Crohn’s disease; reduction of the incidence of hospitalization of
the subject; reduction of the hospitalization length of the subject; and/or ement or
ement of the prophylactic or therapeutic effect(s) of another therapy in the subject. Some
of the ms of Crohn’s disease include abdominal pain, vomiting, diarrhea, rectal ng,
severe al cramps/muscle spasms in the region of the pelvis, weight loss and various
associated complaints or diseases like arthritis, pyoderrna gangrenosum, and primary sclerosing
cholangitis. Symptoms of Crohn’s disease also may include defecation often porridge-like and
sometimes steatorrhea, fever, e, flatulence, bloating, perianal discomfort such itchiness and
pain, fecal incontinence, aphthous ulcers of the mouth, and/or weight loss. In some
embodiments, the compositions described herein prevent the onset or development of one or
more of the above-listed symptoms or other ms known in the art, or reduce duration
and/or severity of one or more of these symptoms.
In some embodiments, the compositions described herein are used to prevent and/or
treat mucositis. Mucositis is the painful inflammation and ulceration of the mucous membranes
lining the digestive tract (e.g., as an adverse effect of chemotherapy or radiotherapy treatment for
cancer). Mucositis can occur anywhere along the gastrointestinal tract, for example, in the
mouth (i.e., oral tis). ACcordingly, in some embodiments, the compositions bed
herein are administered topically to a t (e.g., a t diagnosed with or displaying
symptoms of mucositis) to treat mucositis (e. g., administered topically on the inflamed or
ulcerated area of the mouth, or administered topically to the anus or rectal area such as via a
cream, a suppository, a suspension, a liquid solution, a gel, or an ointment). In some
embodiments, the compositions described herein are administered at the site, or in proximity to
the site, of an inflammation or ulcer caused by or associated with mucositis (e.g., in the mouth).
In specific embodiments, the compositions described herein can be administered daily (e.g., once
or twice a day) until the symptoms of mucositis subside (e.g., for 2, 3, 4, 5, 6, 7, 8, 9, 10 12
, 11,
days, 2 weeks, 3 weeks, 4 weeks, or more than 4 weeks). In certain embodiments, ent of a
subject having mucositis by administration of a composition described herein results in one or.
more of the following: prevention or reduction of frequency of the recurrence vof the mucositis;
reduction in the on and/or ty of one or more symptoms associated with mucositis
(e.g., pain, ulceration); ion in the number of symptoms associated with mucositis;
reduction of the incidence of hospitalization of the subject; reduction of the hospitalization
length of the subject; and/or enhancement or improvement of the prophylactic or therapeutic
effect(s) of another therapy in the subject.
In another specific embodiment, the compositions described herein are used to
prevent and/or treat a viral infection or a disease caused by or associated therewith. Without
being bound by any mechanism of action, the ability of sNAG nanofibers to induce beta
defensins (e.g., beta—defensin 1) may contribute to the anti-viral activity of the sNAG nanoflbers.
Beta defensins (e. g., beta-defensin l) have been shown to have anti-viral activity. Exemplary
s which can cause infection or disease to be prevented and/or treated with the compositions
bed herein e, t limitation, respiratory syncytial virus (RSV), influenza virus
(influenza A virus, influenza B virus, or influenza C virus), human metapneumovirus (HMPV),
rhinovirus, parainfluenza virus, SARS Coronavirus, human irmnunodeficiency virus (HIV),
hepatitis virus (A, B, C), ebola virus, herpes simplex virus (e.g., HSV-1, HSV-2, HSV-6, HSV-
7), varicella, varicella zoster virus, human papillomavirus (HPV), parapox virus, morbilli,
echovirus, adenovirus, Epstein Barr virus, Coxsackie virus, enterovirus, rubella, variola major,
and a minor. In certain embodiments, prevention of a viral infection in a subject or a
e caused by or associated therewith by administration of a composition bed herein
results in one or more of the following: prevention of the development or onset of a disease
caused by or associated with viral ion; and/or prevention of the spread of a viral infection
or a disease caused by or associated therewith from the subject to another subject or population
of subjects. In certain embodiments, treatment of a subject having a viral infection or a disease
caused by or associated therewith by administration of a composition described herein results in
one or more of the following: prevention of the recurrence of the viral infection or a disease
caused by or associated therewith; reduction in the number of ms ated with the viral
infection or a e caused by or ated therewith; reduction in organ failure associated
with the viral infection or a disease caused by or associated therewith; reduction of the severity
and/or duration of the viral infection or a disease caused by or associated therewith; reduction of
the severity and/or duration of one or more ms of the viral infection or a disease caused
by or associated therewith; reduction in viral load or count (e.g., by more than about 0.25 log, 0.5
log, 0.75 log, 1 log, 1.5 log, 2 logs, 2.5 logs, 3 logs, 4 logs, 5 logs, 6 logs, 7 logs, 8 logs, 9 logs,
or 10 logs); reduction of the incidence of hospitalization of the subject; reduction of the
hospitalization length of the t; an se the al of the subject; enhancement or
improvement of the lactic or eutic effect(s) of another therapy in the subject;
tion of the spread of a virus from a cell, tissue, organ of the subject to another cell, tissue,
organ of the subject; prevention of the pment or onset of a disease caused by or associated
with the viral infection, or one or more symptom thereof; and/or prevention ofthe spread of a
viral infection or a disease caused by or associated therewith from the subject to another subject
or population of ts.
In one specific embodiment, the compositions described herein are not used to
prevent and/or treat an HIV infection or a disease caused by or associated with an HIV infection.
Symptoms of a viral infection may e but are not limited to fever, chills,
headache, stiff neck, irritability, enlarged , diarrhea, nausea, vomiting, a skin or a mucous
membrane abnormality associated with a viral infection (e. g, a rash, an ulceration, a cold sore, a
, a swelling, redness, itching, a papule, a vesicle, a pustule, a blister, a crust) and/or pain
associated with such abnormality, abdominal pain, sore throat, ear pain, cough, weight loss,
fatigue, body aches, and/or other flu-like symptoms. In some ments, the compositions
described herein prevent the onset or development of one or more of the above-listed symptoms
or other symptoms known in the art, or reduce duration and/or severity of one or more of these
symptoms.
In another specific embodiment, the compositions bed herein are used to
prevent and/or treat a viral infection of a wound (e.g., an open wound such as an incision, a
laceration, a penetration, an abrasion, or a burn). In another specific embodiment, the
compositions described herein are not used to prevent and/or treat a viral infection of a wound.
There are two types of wounds, open and closed. Open wounds are classified according to the
object that caused the wound. For example, incisions or incised wounds (including surgical
wounds) are caused by a clean, edged object such as a knife, a razor or a glass splinter.
Lacerations are irregular wounds caused by a blunt impact to soft tissue which lies over hard
tissue (e.g., laceration of the skin covering the skull) or tearing of skin and other tissues such as
caused by childbirth. Abrasions or grazes are superficial wounds in which the topmost layer of
the skin (the epidermis) is scraped off. Puncture wounds are caused by an object puncturing the
skin, such as a nail or needle. Penetration wounds are caused by an object such as a knife
entering the body. Gunshot wounds are caused by a bullet or similar projectile g into (e.g.,
entry wound) and/or h the body (e.g. , exit wound). In a medical context, all stab wounds
and gunshot wounds are considered open wounds. Open wounds also e burn wounds
induced by thermal, chemical, or electrical injury. Closed wounds include contusions (more
commonly known as a bruise, caused by blunt force trauma that damages tissue under the skin),
hematoma (also called a blood tumor, caused by damage to a blood vessel that in turn causes
blood to collect under the skin), and crushing injuries (caused by a great or extreme amount of
force applied over a long period of time).
In certain embodiments, the sNAG compositions described herein are used to prevent
and/or treat a topical viral ion in a patient (e.g., in a patient diagnosed with viral infection
or displaying a symptom of a viral infection). In some embodiments, the compositions described
herein are used to prevent and/or treat a viral infection or a symptom of a viral infection on the
skin, mucous membranes (e.g., eyes, ears, throat, vagina, anus), or the surface of other tissues.
In certain embodiments, the compositions described herein are administered directly to the skin,
mucous membrane (e.g., eyes, ears, throat, oral cavity, , anus), or the surface of other
tissues. In some ments, the compositions described herein are used to treat vesicular
(such as a vesicle, a pustule or a blister), ulcer or crust stages of a viral infection (e.g., herpes
simplex virus infection or lla zoster infection). In other embodiments, the compositions
described herein are used to treat me, erythema/macule or papule/edema stages of a viral
infection (e.g., herpes simplex virus infection or varicella zoster infection). In certain
embodiments, the compositions described herein are administered at the site or in the proximity
to the site of a viral infection or at the site or in the proximity to the site of a symptom of a viral
infection (e.g., to a cold sore, lesion, blister, pustule, ulcer, rash, swelling, or crust associated
with a viral ion). In some embodiments, treatment of a subject having a topical viral
infection by administration of a composition described herein results in one or more of the
following: reduction of the severity and/or duration of a symptom of a l viral infection
(e.g., an itching, a , an ulcer, a blister, a papule, a rush, a crust, or any other symptom of a
topical viral infection described herein or known in the art); reduction of pain ated with'a
symptom of a topical viral infection; reduction in the number of ms associated with a
l viral infection; prevention or reduction of frequency of the recurrence of a symptom of a
l viral infection; prevention of the spread of a topical viral infection from the subject to
another subject; prevention of the onset or development of one or more of the symptoms of a
topical viral ion described herein or known in the art; and/or enhancement or improvement
of the lactic or therapeutic effect(s) of another y (e.g., r anti-viral therapy) in
the t. In ular embodiments, the sNAG compositions described herein are formulated
in a rrier form for use in the treatment of topical viral infections. For example, the
compositions described herein are formulated in the form of a liquid solution, a suspension (e.g.,
a thick suspension), a cream, or an ointment for use in the treatment of topical viral infections.
In one embodiment, the sNAG compositions described herein are not in a solid form when used
in the ent of topical viral infections. In yet other embodiments, the sNAG compositions
bed herein are barrier-forming and/or solid for use in the treatment of topical viral
infections. Example 8, infra, shows that sNAG nanofibers are effective to treat l viral
ions based on the data obtained on human patients. In particular, e 8 shows that
sNAG nanofibers are effective to treat an HSV infection, such as a cold sore caused by or
associated with an HSV infection, in human patients. A composition comprising sNAG
nanofibers that can be used to treat a topical viral infection can be any sNAG composition
described herein. In one embodiment, a composition comprising sNAG nanofibers that can be
used to treat a topical viral infection (e. g., HSV) can be the same or similar to the composition
described in Example 8.
Viral ions and diseases/conditions of the skin associated with viral infections
that can be topically treated using the compositions described herein include, but are not limited
to, measles (morbilli), German measles (rubella), chickenpox (varicella), fifth disease (erythema
infectiosum, due to parvovirus), Roseola, ious mononucleosis or glandular fever (Epstein
Barr virus), enterovirus infections, Pityriasis rosea (possibly caused by herpes 6 or 7), hand, foot
and mouth disease (due to Coxsackie infection), Gianotto-Crosti syndrome (papular
acroderrnatitits occurring in children; most often caused by infectious mononucleosis due to
n Barr virus or hepatitis B), Laterothoracic exanthem (asymmetric periflexural exanthem
of childhood or APEC), smallpox, cowpox, epidermodysplasia verruciforrnis, skin conditions
caused by or associated with HIV infections and/or Kaposi’s sarcoma, Rickettsial diseases,
yellow fever (due to flavivirus infection), herpes simplex (cold sores and genital herpes), eczema
herpetcum, herpes zoster (shingles), herpangina/vesicular stomatitis (oral ulcers), molluscum
contagiosum, viral warts (e.g., verrucas, genital warts or condylomas, squamous cell papillomas),
herpetic whitlow, herpes gladiatorum, Orf, and 's nodules.
In a specific embodiment, the compositions described herein are used to t
and/or treat an infection with a herpes x virus (e.g., HSV—1, HSV-2), or a disease or
condition caused by a herpes simplex virus (e.g., HSV-1, HSV-2). Symptoms of Herpes simplex
virus type 1 (HSV-l) may include blisters or lesions in the mouth, throat, lips (e.g., peri-oral cold
sores), and symptoms of herpes simplex virus type 2 (HSV-2) may include blisters or lesions
(e.g., papules and/or vesicles) on the outer surface of genitals. Both types of HSV reside in a
latent state in the sensory nerves of the skin. During an attack, the virus spreads down the nerves
» and out into the skin or mucous membranes where it multiplies, g the clinical lesion. After
each attack it recedes up the nerve fiber and becomes dormant again. During the active phase,
there is considerable shedding of virus and the s are highly contagious. Primary infections
of type 1 occur mainly in infants and young children and are usually mild or subclinical. In
crowded, underdeveloped areas of the world up to 100% of children have been infected by the
age of 5. Type 2 is usually sexually acquired, afier puberty and is less often asymptomatic. The
virus is shed in saliva and genital secretions, during a clinical attack and for some days or weeks
ards. The amount shed from active lesions is 100 to 1,00l) times greater than when it is
inactive. Spread of HSV is usually by direct contact with infected secretions. Where immunity
is deficient infections tend to occur more frequently and to be more nced and persistent.
Recurrence may be triggered by: minor trauma; other infections including coryza, ultraviolet
radiation (sun exposure); hormonal factors (premenstrual flares occur); emotional stress;
operations or procedures performed on the face (including dentistry). Accordingly, in some
embodiments, the compositions described herein are administered topically to treat HSV—1
infection or a lesion or a cold sore associated with HSV-l ion (e.g., stered orally or
peri-orally). In other embodiments, the itions described herein are administered topically
to treat HSV-2 infection or a genital lesion associated with HSV-2 infection (e.g., administered
topically in the genital area, such as lly); In some embodiments, treatment of a subject
having an HSV ion or a disease caused by or associated therewith by administration of a
ition described herein s in one or more of the following: reduction of the severity
and/or duration of a symptom of an HSV infection (e.g., a cold sore, a lesion, or any other
symptom of an HSV infection described herein or known in the art); reduction in the number of
symptoms associated with an HSV ion, reduction of pain associated with a m of an
HSV infection (e.g., a cold sore or a lesion); prevention'or reduction of frequency of the
recurrence of a symptom of an HSV infection; prevention of the spread of an HSV infection
from the subject to another t; prevention of the onset of development of one or more
symptoms of an HSV ion; and/or enhancement or improvement of the prophylactic or
eutic effect(s) of another therapy in the subject. In particular embodiments, a composition
bed herein is administered to a human infant, a human toddler, a human child, a human
adult, and/or an elderly human who has an HSV infection or a symptom of an HSV infection. In
some embodiments, the itions described herein are administered topically on a surface
area (e.g., ral, oral or genital area of the skin or mucous membranes) at the time when the
surface area starts to , itch or swell in tingling, itching or ng at the surface area
is associated with an HSV infection (e.g., HSV-1 or HSV-2)). In some embodiments, the
compositions bed herein are administered topically at the site, or in proximity to the site, of
a cold sore or lesion (e.g., a peri-oral, oral or genital lesion on the skin or on a mucous
membrane) (wherein the cold sore or lesion is associated with an HSV infection (e.g., HSV-l or
HSV-2)). Example 8 shows that a sNAG nanofiber composition was effective to treat cold sores
associated with HSV infection in human patients when applied topically at the site of the cold
sore in a patient, and that treatment of HSV-associated cold sores with a sNAG nanofiber
composition resulted in reduction of the severity and duration of the cold sores, and of the pain
associated with the cold sores. In some embodiments, the compositions described herein are
used to treat vesicular (such as a vesicle, a pustule or a blister), ulcer or crust stages of an HSV
(e.g., HSV-1 or HSV-2) infection. In other ments, the compositions described herein are
used to treat prodrome, erythema/macule or papule/edema stages of an HSV (e.g., HSV-1 or
HSV-2) infection. In certain embodiments, compositions described herein are administered in
combination with an anti-viral drug (e. g., acyclovir or any other anti-viral drug described herein
or known in the art) in the ent of an HSV infection. In specific embodiments, the
compositions described herein can be administered daily’ (e.g., once or twice a day) until the
symptoms of an HSV infection subside (e.g., for 2, 3, 4, 5, 6, 7, 8, 9, 10 12 days, 2 weeks, 3
, ll,
weeks, 4 weeks, or more than 4 weeks).
In a specific embodiment, the compositions described herein are used to t
and/or treat an infection with varicella virus, or a disease or condition caused by varicella virus
(herpes zoster, shingles, or chickenpox). During varicella infection (see Shingles, Clinical
Knowledge Summaries (2008)), which usually occurs ih' childhood, virus is seeded to nerve
cells, usually sensory cells. Herpes zoster or shingles is characterized by distribution in a single
dermatome. It may not affect all of the dermatome but usually it is confined to the area of one
dermatome and does not ore cross the midline. Symptoms of herpes zoster include,
without limitation, a rash, which consists of macules and s, and develops into vesicular
lesions in a dermatomal distribution (most ly on the chest), and pain. The rash tends to
last 7-10 days, and healingcan take 2-4 weeks. More extensive e may occur in immune
compromised patients (for example, with mas and HIV). Herpes zoster can occur at any
age, but it is more common in the elderly, and slightly more common in females (although
chickenpox affects both sexes equally). Skin complications can include secondary infection,
scarring and changes in pigmentation. The elderly are more likely to have complications due to
herpes zoster ially postherpetic gia). ingly, in some embodiments, the
compositions described herein are administered topically to treat herpes zoster infection or
chickenpox (e. g., administered on the skin). In some embodiments, the compositions described
herein are administered at the site, or in proximity to the site, of a rash (e.g., a macule or papule
on the skin) (wherein the rash is associated with herpes zoster infection). In some ments,
treatment of a subject having herpes zoster infection or a disease caused by or ated
therewith by administration of a composition described herein results in one or more of the
following: reduction of the severity and/or duration of a symptom of herpes zoster infection (e.g.,
a rash, or any other symptom of herpes zoster infection listed herein or known in the art);
reduction in the number of symptoms associated with herpes zoster infection; reduction of pain
associated with a symptom of herpes zoster infection; prevention or reduction of frequency of the
recurrence of a m of herpes zoster infection; prevention of the spread of herpes zoster
infection from the subject to another subject; prevention of the onset or development of a
symptom of herpes zoster infection; and/or enhancement or improvement of the prophylactic or
therapeutic effect(s) of another therapy (e.g., another anti-viral therapy) in the subject. In
particular embodiments, a composition described herein is administered to a human infant, a
human toddler, a human child, a human adult, and/or an elderly human who has herpes zoster
infection or a symptom of herpes zoster infection. In certain ments, itions
described herein are administered in combination with an anti-viral drug (e.g., acyclovir or any
other anti—viral drug described herein or known in the art) in the treatment of herpes zoster
infection. In specific embodiments, the compositions described herein can be administered daily
WO 42581
(e.g., once or twice a day) until the symptoms of herpes zoster infection e (e.g., for 2, 3, 4,
, 6, 7, 8, 9, 10 12 days, 2 weeks, 3 weeks, 4 weeks, or more than 4 weeks).
, ll,
In r specific embodiment, the itions described herein are used to
prevent and/or treat molluscum contagiosum ion. Molluscum contagiosum is common and
usually affects infants and young children, and, only rarely, adults (see cum contagiosum.
Clinical dge Summaries (2008)). Symptoms of molluscum contagiosum include, but are
not limited to, clusters of small papules, ularly, in the warm moist places such as the axilla,
groin or behind the knees. The papules range in size from 1-6 mm and may be white, pink or
brown. They often have a waxy, pinkish look and are ~umbilicated (a l depression of the
surface). As they resolve, they may become inflamed, crusted or scabby. They may number a
few or several hundred on any individual. The disease may persist for months or occasionally
for a couple of years. Rarely, it may leave tiny pit-like scars (induration). Molluscum
contagiosum can be spread from person to person, usually among children, by direct skin
contact; and sexual contact in adults may transmit infection. s tend to be more numerous
and more persistent in children with atopic eczema and in HIV-infected patients. In children,
lesions are common on the face and trunk. ingly, in some embodiments, the
compositions described herein are administered topically to treat molluscum contagiosum
infection (e.g., administered on the skin). In some embodiments, the compositions described
herein are administered at the site, or in proximity to the site, of a rash (e.g., a macule or papule
on the skin) (wherein the rash is associated with molluscum contagiosum infection). In some
embodiments, treatment of a subject having molluscum contagiosum or a disease caused by or
associated therewith by administration of a composition described herein results in one or more
of the following: reduction of the severity and/or duration of a symptom of molluscum
contagiosum (e.g., a rash, or any other symptom of molluscum contagiosum listed herein or
known in the art); reduction in the number of symptoms of molluscum contagiosum; reduction of
pain associated with a symptom of molluscum contagiosum; prevention or reduction of
frequency of the recurrence of a symptom of molluscum contagiosum; prevention of the spread
of molluscum contagiosum from the subject to another subject; tion of the onset or
development of a m of molluscum contagiosum; and/or enhancement or improvement of
the prophylactic or therapeutic (s) of another therapy in the subject. In particular
embodiments, a composition described herein is administered to a human infant, a human
toddler, a human child, a human adult, and/or an elderly human who has molluscum
contagiosum or a symptom of molluscum iosum. In certain embodiments, compositions
described herein are administered in combination with a known therapy (e.g.,, squeezing,
piercing, curettage, erapy, wart paints such as salicylic acid and podophyllin;
immunomodulatory agent such as imiquimod cream; 1% hydrocortisone cream; or fusidic acid
cream 2%) in the treatment of molluscum contagiosum infection. In specific embodiments, the
compositions described herein can be administered daily (e.g., once or twice a day) until the
symptoms of molluscum contagiosum infection subside (e.g., for 2, 3, 4, 5, 6, 7, 8, 9, 10 12
, 11,
days, 2 weeks, 3 weeks, 4 weeks, or more than 4 weeks).
In another specific embodiment, the compositions bed herein are used to
prevent and/or treat human papillomavirus or warts or verrucae associated with human
papillomavirus. More than 80 HPV es are known (see Warts and verrucae, Clinical
Knowledge Summaries (June 2009)), of which 20 can affect the l tract. The presentation
and appearance of HPV infection varies according to the site of infection. For example, plantar
warts occur on pressure-bearing areas and are flattened rather than raised. Warts are most
common in childhood and are spread by direct contact or auto-inoculation; it may take up to 12
months for the wart to appear. HPV warts are more nt and more troublesome in
association with immunosuppression, and are more infectious when they are wet or when they
bleed from trauma (e.g. scratching). HPV infection is more persistent in adults than in children.
Accordingly, in some embodiments, the compositions described herein are administered
topically to treat HPV ion or warts or verrucae associated with HPV infection (e.g.,
administered on the skin). In some embodiments, the compositions described herein are
administered at the site, or in proximity to the site, of a wart or verricuae (wherein the wart or
verricuae is caused by or associated with HPV). In some embodiments, treatment of a t
having HPV infection or a disease caused by or associated ith by stration of a
composition described herein results in one or more of the following: reduction of the ty
and/or duration of a symptom of HPV infection (e.g., a wart, a verricuae, or any other symptom
of HPV infection described herein or known in the art); reduction in the number of symptoms
associated with HPV infection; reduction of pain associated with a symptom of HPV infection;
prevention or ion of frequency of the recurrence of a m of HPV infection;
prevention of the spread ofHPV infection from the subject to another subject; prevention of the
2012/033782
onset or development of a m of HPV infection; and/or enhancement or improvement of
the prophylactic or therapeutic effect(s) of another therapy in the subject. . In particular
embodiments, a composition described herein is administered to a human infant, a human
toddler, a human child, a human adult, and/or an elderly human who has HPV infection or a
symptom ofHPV infection. In specific embodiments, the compositions described herein can be
administered daily (e. g., once or twice a day) until the symptoms of HPV infection subside (e.g.,
for 2, 3, 4, 5, 6, 7, 8, 9, 10 12 days, 2 weeks, 3 weeks, 4 weeks, or more than 4 weeks).
, 11,
In another specific ment, the compositions described herein are used to
prevent and/or treat orf. Orf is contracted from sheep and goats (see Orf, Health Protection
Agency (2010)). It is caused by a parapox virus, which infects mainly young lambs and goats
that contract the infection from one another (or ly from persistence of the virus in the
pastures). Human lesions are caused by direct inoculation of infected material. It may occur in
farmers, butchers, vets, children who bottle-feed lambs and ly even children who play in
pastures where sheep have grazed. The incubation period of parapox virus is 5 or 6 days. Orf
lesions are y solitary but multiple lesions do occur. Orf lesions are usually small, firm, red
or reddish-blue, forming a lump that enlarges to form a flat-topped, blood-tinged pustule or
blister. The fiilly developed lesion is usually 2 or 3 cm in diameter but may be as large as 5 cm;
and although there appears to be pus under the white skin, incising this will reveal firm, red
tissue underneath. The lesion is sometimes irritable during the early stages and is often tender.
They usually occur on the fingers, hands or forearms, but may also occur on the face. Red
lymph lines may occur on the medial side of the elbow up to the axilla. There may be a mild
fever associated with orf. ingly, in some embodiments, the compositions described
herein are administered topically to treat orf (e.g., administered on the skin). In some
embodiments, the compositions described herein are administered at the site, or in proximity to
the site, of a lesion, a e or a blister (wherein the lesion, pustule or blister is caused by or
associated with orf). In some embodiments, ent of a t having orf by administration
of a composition described herein results in one or more of the following: ion of the
severity and/or on of a m of orf (e.g., a lesion, a pustule, a blister, or any other
symptom of orf bed herein or known in the art); reduction in the number of symptoms
associated with orf; reduction of pain associated with a symptom of orf; prevention or reduction
of frequency of the recurrence of a symptom of orf; prevention of the spread of orf from the
subject to another subject; prevention of the onset or development of a symptom of orf; and/or
enhancement or ement of the prophylactic or therapeutic (s) of another therapy in
the subject. In particular embodiments, a composition described herein is administered to a
human infant, a human toddler, a human child, a human adult, and/or an elderly human who has
orf or a m of orf. In specific embodiments, the compositions described herein can be
administered daily (e.g., once or twice a day) until the ms of orf subside (e.g., for 2, 3, 4,
, 6, 7, 8, 9, 10 12 days, 2 weeks, 3 weeks, 4 weeks, or more than 4 weeks).
, 11,
In certain’embodiments, the compositions described herein are used to treat viral
infections that produce rashes. Examples of viral infections that produce rashes include, but are
not limited to, measles lli), German measles (rubella), chickenpox (varicella virus), fifth
e (erythema infectiosum, due to parvovirus), Roseola (erythema subitum, due to herpes
virus 6), asis rosea (the cause is unknown but it may be caused by herpes virus types 6 and
7), echovirus and adenovirus infections, Epstein Barr virus of infectious mononucleosis or
glandular fever, and primary HIV infection. In certain ments, the compositions described
herein are used to treat nonspecific rashes associated with viral infections (e. g., erythematous
rash such as erythematous y eruption). In some embodiments, the compositions described
herein are administered at the site of a rash caused by or associated with a viral infection or in
proximity to the site of a rash caused by or associated with a viral infection. In certain
embodiments, the compositions described herein reduce the severity of rashes, the duration of
rashes, and/or pain associated with rashes caused by a viral infection.
] In another specific embodiment, the compositions described herein are used to
prevent and/or treat hand, foot and mouth disease or an infection caused by Coxsackie virus or
enterovirus. Hand, foot and mouth disease is common, mild and brief, most often affecting
young children during the summer months (see Hand, foot and mouth disease, Clinical
Knowledge Summaries (March 2010)). Hand, foot and mouth disease is caused by Coxsackie
virus A16, although it can also be due to enterovirus 71’. Incubation period of such s is 3-5
days. Symptoms of hand, foot and mouth disease include small, flat blisters on the hands and
feet, oral ulcers, that are sometimes painful, and the disease may be accompanied by a mild fever
or a rash on the ks (in young children). Accordingly, in some embodiments, the
compositions described herein are administered topically to treat hand, foot and mouth disease or
a ion caused by or associated with Coxsackie virus or enterovirus infection (e. g.,
WO 42581
administered on the skin). In some embodiments, the compositions described herein are
administered at the site, or in proximity to the site, of a blister, ulcer or rash (wherein the blister,
ulcer or rash is associated with hand, foot and mouth disease or a condition caused by or
associated with Coxsackie virus or enterovirus infection). In some embodiments, treatment of a
subject having hand, foot and mouth disease by administration of a composition described herein
results in one or more of the following: reduction of the severity and/or duration of a symptom of
hand, foot and mouth disease (e.g., a rash, a blister, an ulcer or any other symptom of hand, foot
and mouth disease described herein or known in the art); reduction in the number of symptoms
of hand, foot and mouth disease; reduction of pain associated with a symptom of hand, foot and
mouth disease; prevention or reduction of frequency of the ence of a symptom of hand,
foot and mouth disease; prevention of the spread of hand, foot and mouth disease from the
subject to another subject; prevention of the onset or development of a symptom of hand, foot
and mouth disease; and/or enhancement or improvement of the prophylactic or therapeutic
effect(s) of r therapy in the t. In particular embodiments, a ition described
herein is administered to a human infant, a human toddler, a human child, a human adult, and/or
an elderly human who has hand, foot and mouth disease or a symptom of hand, foot and mouth
disease. In specific embodiments, the compositions described herein can be administered daily
(e.g., once or twice a day) until the symptoms of hand, foot and mouth disease subside (e.g., for
2, 3, 4, 5, 6, 7, 8, 9, 10 12 days, 2 weeks, 3 weeks, 4 weeks, or more than 4 weeks).
, 11,
In another specific ment, the itions described herein are used to
prevent and/or treat Crosti-Gianotti me. Crosti-Gianotti syndrome is a response of the skin
to viral infection with a r rash which lasts for several weeks. This condition is also known
as papulovesicular acrodermatitis of childhood, papular rmatitis of ood and
acrodermatitis papulosa infantum. Crosti-Gianotti syndrome can be caused by Hepatitis B virus,
Epstein Barr virus, Coxsackie viruses, Echoviruses, or Respiratory syncytial virus. It affects
children between 6 and 12 months. In this condition, a profuse on of dull red spots may
develop over 3 or 4 days. They usually appear first on the thighs and buttocks, then on the outer
aspects of the arms and finally on the face, often in an asymmetrical pattern (see Chuh, Cutis
68(3):207-13 (2001)). The spots may be 5-10 mm in diameter, may have a deep red color or
purple color (especially on the legs, due to leakage of blood from the capillaries), and may
develop into fluid-filled blisters. Accordingly, in some ments, the compositions
described herein are administered topically to treat -Gianotti syndrome (e.g., administered
on the skin). In some embodiments, the itions described herein are administered at the
site, or in proximity to the site, of a red spot, eruption or rash (wherein the red spot, eruption or
rash is associated with Crosti-Gianotti syndrome or an infection caused by Hepatitis B virus,
Epstein Barr virus, Coxsackie viruses, Echoviruses, or Respiratory syncytial virus). In some
embodiments, treatment of a subject having Crosti-Gianotti syndrome by stration of a
composition bed herein results in one or more of the following: reduction of the severity
and/or duration of a m of -Gianotti syndrome (e.g., a red spot, an eruption, a rash or
any other symptom of Crosti-Gianotti syndrome described herein or known in the art); reduction
in the number of symptoms associated with Crosti-Gianotti me; reduction of pain
associated with a m of Crosti-Gianotti syndrome; prevention or reduction of frequency of
the recurrence of a symptom of Crosti-Gianotti syndrome; prevention of the spread of Crosti-
Gianotti syndrome from the subject to another subject; prevention of the onset or development of
a symptom of Crosti-Gianotti; and/or enhancement or improvement of the prophylactic or
therapeutic effect(s) of another therapy in the subject. In particular embodiments, a composition
described herein is stered to a human infant cularly, to an infant between 6 and 12
months of age), a human toddler, a human child, a human adult, and/or an elderly human who
has Crosti-Gianotti syndrome or a symptom thereof. In specific embodiments, the compositions
described herein can be administered daily (e.g., once or twice a day) until the symptoms of
-Gianotti syndrome subside (e.g., for 2, 3, 4, 5, 6, 7, 8, 9, 10 12 days, 2 weeks, 3
, 11,
weeks, 4 weeks, or more than 4 weeks).
In another specific embodiment, the compositions bed herein are used to
prevent and/or treat herpes torum or “scrum pox.” Herpes gladiatorum is primarily
transmitted by direct skin-to-skin contact and abrasions may facilitate a portal of entry (see
Becker et al., Am J Sports Med. 16(6):665-9 (1988)). The majority of lesions due to herpes
gladiatorum occur on the head or face, followed by the trunk and extremities. Symptoms of
herpes gladiatorum e, but are not limited to, prodromal itching or burning sensation, which
may be followed by clustered vesicles on an matous base which heal with crusts over
about 1 to 2 weeks. Other, less common, symptoms of herpes gladiatorum include, without
limitation, headache, malaise, sore throat and fever. Recurrent episodes may follow the initial
infection. Accurate diagnosis can be made by viral immunofluorescence, and cultures can be
obtained by gently breaking an intact vesicle and firmly rubbing the swab tip across the base of
the erosion. Accordingly, in some embodiments, the compositions described herein are
administered topically to treat herpes torum infection (e.g., administered on the skin). In
some embodiments, the compositions described herein are administered at the site, or in
proximity to the site, of an itching, a lesion, a vesicle or a crust (wherein the site of itching, a
lesion, a vesicle or a crust is caused by or associated with herpes gladiatorum infection). In
certain embodiments, compositions bed herein are administered in combination with an
anti-viral drug (e.g., acyclovir or any other anti-viral drug described herein or known in the art)
in the treatment of herpes gladiatorum infection. In some embodiments, treatment of a subject
having herpes gladiatorum by administration of a composition described herein results in one or
more of the following: reduction of the severity and/or duration of a symptom of herpes
gladiatorum (e.g., an itching, a lesion, a vesicle, a crust, or any other symptom of HPV ion
described herein or known in the art); reduction in the number of symptoms ated with
herpes gladiatorum; reduction of pain associated with a symptom of herpes gladiatorum;
prevention of the recurrence of a m of herpes gladiatorum; prevention of the spread of
herpes gladiatorum from the subject to another subject; prevention of the onset or development
of a symptom of herpes gladiatorum; and/or enhancement or improvement of the prophylactic or
therapeutic effect(s) of another y in the subject. In particular embodiments, a composition
described herein is administered to a human infant, a human toddler, a human child, a human
adult, and/or an elderly human who has herpes gladiatorum or a symptom of herpes gladiatorum.
In specific embodiments, a composition described herein is administered to an athlete (e. g.,
professional athlete) for a prophylactic and/or therapeutic purpose. In specific ments, the
compositions described herein can be administered daily (e.g., once or twice a day) until the
ms of herpes torum infection subside (e.g., for 2, 3, 4, 5, 6, 7, 8, 9, 10 , ll, 12 days,
2 weeks, 3 weeks, 4 weeks, or more than 4 .
] In another specific embodiment, the compositions described herein are used to
prevent and/or treat common warts associated with a viral infection (e. g., plantar warts, warts in
es). In some embodiments, the compositions described herein are administered at the site,
or in proximity to the site, of a wart caused by or associated with a viral infection or in proximity
to the site of a wart caused by or associated with a viral infection. In n embodiments, the
WO 42581
compositions described herein reduce the number of warts, the severity of warts, the duration of
warts and/or the pain associated with warts caused by a viral infection.
In n embodiments, the compositions bed herein are used to prevent and/or
treat viral infections in immunocompromised patients (e. g., HIV-infected patients).
In some embodiments, the compositions described herein are used to treat
gastroenteritis (e.g., gastroenteritis caused by or associated with a viral infection, or
gastroenteritis caused by or ated with a protozoallinfection). es of viruses that can
cause gastroenteritis include but are not limited to rotavirus, rus, adenovirus, and
astrovirus. Examples of protozoa that can cause gastroeneteritis include but are not limited to
Giardia Iamblia, cryptosporidium, and Entamoeba histolytica. In one ment, the
compositions described herein are administered rectally (e.g., as a cream or suppository) to treat
gastroenteritis. In certain embodiments, treatment of a subject having gastroenteritis by
administration of a composition described herein results in one or more of the following:
prevention of the recurrence of gastroenteritis; reduction in the duration and/or severity of one or
more symptoms associated with gastroenteritis; reduction in the number of symptoms associated
with gastroenteritis; reduction of the incidence of alization of the subject; reduction of the
hospitalization length of the subject; and/or enhancement or improvement of the prophylactic or
eutic effect(s) of another therapy in the subject.
In another specific embodiment, the compositions described herein are used to
prevent and/or treat a fungal infection or a disease caused by or associated ith. Without
being bound by any mechanism of action, the ability of sNAG nanofibers to induce beta
defensins (e.g., beta-defensin 1) may bute to the anti-fungal activity of the sNAG
nanofibers. Beta defensins (e.g., beta-defensin l) have been shown to have anti-fungal activity.
Exemplary fungi which can cause ion or disease to be prevented and/or treated with the
compositions described herein include, without limitation, Blastomyces, ccidiodes,
Sporothrix, Cryptococcus, Candida, Aspergillus, Histoplasma, Cryptococcus, ris,
hialophora, Cladosporium, Drechslera, Exophiala, Fonsecaea, Phialophora, Xylohypha,
Ochroconis, Rhinocladiella, Scolecobasidium, and Wangiella. In certain embodiments,
prevention of a fimgal infection in a subject or a disease caused by or associated therewith by
administration of a composition described herein results in one or more of the following:
prevention of the development or onset of a disease [caused by or associated with fungal
infection; and/or prevention of the spread of a fungal ion or a disease caused by or
associated therewith from the subject to r subject or population of subjects. In certain
embodiments, treatment of a subject having a fungal infection or a disease caused by or
associated therewith by administration of a composition described herein results in one or more
of the following: prevention of the recurrence of the fungal infection or a disease caused by or
ated therewith; reduction in the number of symptoms associated with the fimgal infection
or a disease caused by or associated therewith; reduction in organ failure associated with the
fungal infection or a disease caused by or associated therewith; reduction of the duration and/or
severity of the fungal infection or a disease caused by or associated therewith; reduction of the
duration and/or severity of one or more symptoms of the fungal infection or a disease caused by
or associated therewith; ion in fungal cell count; reduction of the nce of
hospitalization of the subject; reduction of the hospitalization length of the subject; an increase
the survival of the subject; enhancement or improvement of the prophylactic or therapeutic
effect(s) of another therapy in the subject; tion of the spread of a fungus from a cell,
tissue, organ of the subject to another cell, tissue, organ of the subject; prevention of the
development or onset of a disease caused by or associated with the fungal infection, or one or
more symptoms thereof; and/or prevention of the spread of a fungal infection or a disease caused
by or associated ith from the subject to another subject or population of ts.
Symptoms of a fungal infection with jock itch may include itching in the groin are
and/or a red scaly rash. ms of athlete’s foot may include scaling, flaking of the skin,
itching of the feet and/or yelowish toenails. Symptoms of a l infection may include
itching and irritation, burning with urination, and/or thick vaginal rge. Symptoms of
fungal gastroenteritis may include vomiting and/or diarrhea. Symptoms of a fungal infection of
the lungs may include fever, cough and/or ms of pneumonia. Symptoms of mouth yeast
infection (thrush, Candidiasis) may include yellow-white patchy lesions/sores in the mouth or
tongue. Symptoms of Candidiasis of the genitalia (e. g., vagina, vulvae, penis) include itching,
burning, soreness, irritation and/or discharge. In some embodiments, the compositions described
herein prevent the onset or development of one or more of the above-listed ms or other
symptoms known in the art, or reduce on and/or severity of one or more of these
symptoms.
WO 42581
] In some embodiments, the compositions described herein are used to prevent and/or
treat Athlete’s foot, jock itch, ringworm, or a fungal infection of nail, scalp or hair. These fungal
infections can cause reddening, peeling, blistering, and scaling of the skin, itching, deformation
and brittleness of ed nails, and/or brittle hair. They are caused by dermatophytes, a group
of fungi that includes Trichophyton, Microsporum, and Epiderrnophyton species.
Dermatophytes feed on n and rarely penetrate below the skin. Athlete’s foot (tinea pedis)
is found between the toes and sometimes covers the bottom of the foot. Jock itch (tinea cruris)
may extend from the groin to the inner thigh. Scalp and hair infection (tinea capitis) affects hair
shaft, primarily in children. Finger or l infection (tinea m) typically afi‘ects ls
but may also affect fingernails. Ringworm of the body (tinea corporis) can be found anywhere
on the body. Barber’s itch (tinea barbae) affects the bearded portion of the face. In particular
embodiments, the compositions bed herein are administered topically to treat any of the
listed fungal infections (such as Athlete’s foot, jock itch, nail, scalp and hair infections).
In one embodiment, the compositions described herein are administered at the site, or in the
proximity to the site, of ing, peeling, blistering, or scaling of the skin, or itching,
deformation or brittleness of the nail (wherein such symptoms are associated with a fungal
infection). In some ments, treatment of a t having one of the above-listed fungal
infections by administration of a composition described herein results in one or more of the
following: reduction of the severity and/or duration of a symptom of the fungal infection (e.g.,
itching, reddening, g, blistering, or any other symptom of the fungal ion described
herein or known in the art); reduction in the number of symptoms of the fungal infection;
reduction of pain associated with a symptom of the fungal infection; prevention of the recurrence
of a symptom of the fungal infection; prevention of the spread of the fungal infection from the
subject to another subject; prevention of the onset or development of a symptom of the fungal
infection; and/or enhancement or improvement of the prophylactic and/or therapeutic effect(s) of
r therapy (e.g., anti-fungal therapy) in the subject. In particular embodiments, a
composition described herein is administered to a human infant, a human toddler, a human child,
a human adult, and/or an elderly human who has one of the above-listed fungal infections or a
symptom thereof. In specific embodiments, the compositions described herein can be
administered daily (e.g., once or twice a day) until the symptoms of a fimgal infection subside
(e.g., for 2, 3, 4, 5, 6, 7, 8, 9, 10 12 days, 2 weeks, 3 weeks, 4 weeks, or more than 4 weeks).
, 11,
In some embodiments, the compositions described herein are used to prevent and/or
treat Sporotrichosis. Sporotrichosis is a condition caused by the fungus Sporothrix schenckii,
which is not a dermatophyte. It is an infection of the skin and subcutaneous tissue that has been
abraded by thorny plants, pine needles, and Sphagnum moss where this fungus normally resides.
In ular embodiments, the compositions described herein are administered topically to treat
Aporotrichosis. In one embodiment, the compositions described herein are administered at the
site, or in the proximity to the site, of Sporotrichosis infection. In some embodiments, treatment
of a subject having Sporotrichosis by administration of a ition described herein results in
one or more of the following: reduction of the severity and/or duration of a m of
Sporotrichosis, ion in the number of symptoms of Sporotrichosis; reduction of pain
associated with a symptom of Sporotrichosis; prevention or reduction of frequency of the
recurrence of a symptom of richosis; prevention of the spread of Sporotrichosis from the
subject to another subject; prevention of the onset or development of a symptom of
Sporotrichosis; and/or enhancement or improvement of the prophylactic and/or therapeutic
effect(s) of another therapy (e.g., anti-fungal therapy) in the subject. In specific embodiments,
the compositions described herein can be administered daily (e.g., once or twice a day) until the
symptoms of Sporotrichosis subside (e.g., for 2, 3, , 7, 8, 9, 10 12 days, 2 weeks, 3
, 11,
weeks, 4 weeks, or more than 4 weeks).
In another specific embodiment, the compositions described herein are used to
prevent and/or treat a fungal infection of a wound (e.g., an open wound such as an incision, a
laceration, a ation, an on, or a burn). In another specific embodiment, the
compositions described herein are not used to prevent and/or treat a fungal infection of a wound.
In r specific embodiment, the compositions described herein are used to
prevent and/or treat a yeast infection or a disease caused by or associated therewith. Without
being bound by any mechanism of action, the ability of sNAG nanofibers to induce beta
defensins may contribute to the anti-yeast activity of the sNAG nanofibers. Beta ins have
been shown to have east activity. Exemplary yeast which can cause infection or disease to
be prevented and/or treated with the compositions described herein include, without limitation,
Aciculoconidium, Botryoascus, Brettanomyces, Bullera, Bulleromyces, Candida, Citeromyces,
Clavispora, Cryptococcus, lobasidium, Debaromyces, Debaryomyces, a,
Dipodascus, Endomyces, Endomycopsis, obasidium, yces, Filobasidiurn,
Guillierrnondella, Hanseniaspora, Hansenula, Hasegawaea, Hyphopichia, Issatchenkia,
Kloeckera, Kluyveromyces, Komagataella, Leucosporidium, Lipomyces, Lodderomyces,
Malassezia - Mastigomyces, Metschnikowia, Mrakia, Nadsonia, Octosporomyces, idium,
Pachysolen, Petasospora, Phaffia, Pichia, Pseudozyma, Rhodosporidium, Rhodotorula,
Saccharomyces, Saccharomycodes, Saccharomycopsis',‘Schizoblastosporion,
Schizosaccharomyces, Schwanniomyces, Selenotila, Sirobasidium, Sporidiobolus,
Sporobolomyces, Stephanoascus, Sterigmatomyces, ospora, Torulaspora, Torulopsis,
Tremelloid, Trichosporon, Trigonopsis, Udeniomyces, Waltomyces, Wickerhamia, Williopsis,
Wingea, Yarrowia, Zygofabospora, Zygolipomyces, or Zygosaccharomyces. In certain
embodiments, prevention of a yeast ion of a subject or a disease caused by or associated
therewith by administration of a ition bed herein results in one or more of the
following: prevention of the development or onset of a disease caused by or associated with a
yeast ion; and/or prevention of the spread of a yeast infection or a disease caused by or
associated therewith from the subject to another subject or population of subjects. In certain
embodiments, treatment of a subject having a yeast infection or a disease caused by or associated
therewith by administration of a composition described herein s in one or more of the
following: prevention of the recurrence of the yeast infection or a disease caused by or
associated therewith; reduction in the number of symptoms ated with the yeast infection or
a disease caused by or associated therewith; ion in organ failure associated with the yeast
infection or a disease caused by or ated ith; reduction of the duration and/or severity
of the yeast infection or a disease caused by or associated therewith; reduction of the duration
and/or severity of one or more symptoms of the yeast infection or a disease caused by or
ated therewith; ion in yeast cell count; ion of the incidence of hospitalization
of the subject; reduction of the hospitalization length of the subject; an increase the survival of
the subject; enhancement or improvement of the prophylactic or eutic effect(s) of another
therapy in the subject; prevention of the spread of a yeast from a cell, tissue, organ of the subject
to r cell, tissue, organ of the subject; prevention of the development or onset of a disease
caused by or associated with the yeast infection, or one or more ms thereof; and/or
prevention of the spread of a yeast infection or a disease caused by or associated therewith from
the subject to another subject or population of subjects.
In some embodiments, the compositions described herein are used to prevent and/or
treat Candidiasis. Candidiasis is a common yeast infection that is due ily to the
overgrth of Candida ns and other species of Candida, which are part of the normal
flora. In the mouth, candidiasis causes redness and white patches and is called “thrush.” In
children, Candida can cause diaper rash. In women, it can cause genital itching and vaginal
rge that is referred to as a “yeast infection.” Candidiasis can also cause a variety of other
infections, including nail ions, and can become systemic — especially in those who are
immunocompromised. It is currently the fourth most common cause of hospital-acquired
septicemia in the United States. In particular embodiments, the compositions described herein
are administered lly to treat Candidiasis (e.g, administered topically to the skin or topically
to the genital area, such as intravaginally). In one embodiment, the compositions described
herein are administered at the site, or in the ity to the site, of redness, white s or
genital itching (wherein such symptoms are associated with Candidiasis). In some embodiments,
treatment of a subject having Candidiasis by administration of a composition described herein
results in one or more of the following: reduction of the severity and/or duration of a symptom of
Candidiasis, reduction in the number of symptoms of Candidiasis; reduction of pain associated
with a symptom of Candidiasis; prevention or reduction‘of frequency of the recurrence of a
symptom of Candidiasis; prevention of the spread of Candidiasis from the subject to r
subject; prevention of the onset or development of a m of Candidiasis; and/or
enhancement or ement of the prophylactic and/or therapeutic (s) of another therapy
(e.g., anti-yeast therapy) in the subject. In specific embodiments, the compositions described
herein can be administered daily (e. g., once or twice a day) until the symptoms of a Candida
infection subside (e.g., for 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12 days, 2 weeks, 3 weeks, 4 weeks, or
more than 4 weeks).
In some embodiments, the compositions described herein are used to prevent and/or
treat Tinea olor. Symptoms of Tinea versicolor include, but are not limited to,
multicolored patches or lesions on the skin. It is a condition that is common in young adults. In
particular embodiments, the compositions described herein are administered topically to treat
Tinea versicolor. In one embodiment, the compositions. described herein are stered at the
site, or in the proximity to the site, of Tinea versicolor infection. In some embodiments,
treatment of a subject having Tinea versicolor by administration of a composition described
herein results in one or more of the ing: reduction of the severity and/or duration of a
symptom of Tinea olor, reduction in the number of symptoms of Tinea versicolor;
reduction of pain associated with a symptom of Tinea versicolor; prevention or reduction of
frequency of the recurrence of a symptom of Tinea versicolor; prevention of the spread of Tinea
versicolor from the subject to another subject; prevention of the onset or development of a
symptom of Tinea versicolor; and/or enhancement or improvement of the prophylactic and/or
therapeutic effect(s) of another therapy (e.g., anti-yeast therapy) in the subject. In specific
embodiments, the compositions described herein can be administered daily (e.g., once or twice a
day) until the symptoms of a Tinea olor ion subside (e.g., for 2, 3, 4, 5, 6, 7, 8, 9, 10 ,
ll, 12 days, 2 weeks, 3 weeks, 4 weeks, or more than 4- weeks).
In some embodiments, the compositions described herein are used to t and/or
treat osteomyelitis. Osteomyelitis is an infection of the bone or bone marrow, which can be
caused by a bacteria or a fungus Osteomyeltitis can be diagnosed based on ogic results
showing a lytic center with a ring of sclerosis, and culture of material can taken from a bone
biopsy to identify the specific pathogen. ingly, in some embodiments, the compositions
described herein are administered to a t having (e.g., diagnosed with) osteomyelitis to treat
osteomyelitis. In specific embodiments, the compositions described herein are used to treat
osteomyelitis caused by a fungal infection. In a particular embodiment, the compositions
described herein are used to treat an infection, wherein the infection is not caused by a bacteria.
Yet in other embodiments, the compositions described herein are used to treat osteomyelitis
caused by any infection (including, but not limited to, a bacterial infection). In specific
embodiments, the compostions bed herein are administered topically to a surface of a
tissue (e.g., to the surface of a bone or in proximity to the surface of a bone) of a patient after
surgery. For example, the compositions described herein can be administered to an area of the
knee after knee replacement surgery, to an area of the hip after hip replacement surgery, or to an
area of the elbow after elbow replacement surgery. In certain embodiments, treatment of a
subject having osteomyelitis by stration of a composition described herein results in one
or more of the following: ion in the duration and/or severity of one or more symptoms
associated with osteomyelitis (e.g., pain, inflammation); reduction in the number of symptoms
associated with osteomyelitis; tion or reduction of frequency or recurrence of
osteomyelitis; reduction of the incidence of alization of the subject; reduction of the
hospitalization length of the subject; and/or enhancement or improvement of the prophylactic or
therapeutic (s) of another therapy in the subject.
In another c embodiment, the compositions described herein are used to
prevent and/or treat a yeast infection of a wound (e.g., an open wound such as an incision, a
laceration, a penetration, an abrasion, or a burn). In another specific embodiment, the
compositions bed herein are not used to prevent and/or treat a yeast ion of a wound.
In specific embodiments, a subject treated for a viral infection, a fungal infection or
an yeast infection (such as any of the viral, fungal or yeast infections described herein) using the
sNAG compositions described herein does not have a bacterial infection. In other embodiments,
a t treated for a viral, a fiingal, or an yeast infection (such as any of the viral, fungal or
yeast infections described herein) using the sNAG compositions described herein has both a
bacterial infection and a viral, a fungal or an yeast infection. In some embodiments, such
ions are in the same location in the subject’s organism. Inother embodiments, such
infections are in different locations in the subject’s organism.
In certain embodiments, the compositions described herein are used to treat skin
diseases. Without being bound by any mechanism of action, the ability of sNAG nanofibers to
induce beta defensins may contribute to the activity of the sNAG nanofibers in treatment of skin
diseases. Beta defensins have been shown to have activity in skin es. In a specific
embodiment, the compositions described herein are used to treat dermatitis (e.g., atopic
dermatitis). In a specific embodiment, the itions are used to prevent and/or treat atopic
dermatitis in a ure human infant, a human infant, a human toddler, or a hmnan child. In
r specific embodiment, the compositions described herein are used to treat psoriasis (e. g.,
Psoriasis vulgaris, Psoriasis erythroderma, Pustular psoriasis, nail psoriasis, or guttate psoriasis).
[In a specific ment, the, compositions are used to treat psoriasis in a premature human
infant, a human infant, a human toddler, or a human child. In certain embodiments, treatment of
a subject having a skin disease by administration of a composition described herein results in one
or more of the ing: prevention of the recurrence of the skin disease; ion in the
number of symptoms associated with the skin e; reduction in the ty or duration of
one or more symptoms associated with the skin disease; reduction of the incidence of
hospitalization of the subject; reduction of the hospitalization length of the subject; and/or
enhancement or improvement of the prophylactic or therapeutic effect(s) of another therapy in
the subject.
ms of itis include but are not limited to rashes (e.g., a bumpy rash),
blisters, redness of the skin, swelling, itching, skin lesions, , and/or scarring. Such
symptoms often appear on the neck, wrist, forearm, thigh or ankle; but may also appear on the
l area. Common symptoms of atopic dermatitis include but are not limited to dry, itchy,
and/or red skin. Symptoms of psoriasis include but are not limited to plaques (e.g., raised areas
of inflamed skin covered with silvery white scaly skin), itching, swelling, pain, pustules (e.g.,
raised bumps filled with ectious pus), smooth d patches of skin, small scaly
lesions, and/or thickening and discoloring of the nails. In some embodiments, the compositions
described herein prevent the onset or development of one or more of the above-listed symptoms
or other symptoms known in the art, or reduce duration and/or severity of one or more of these
symptoms.
In a specific embodiment, a composition bed herein is not used to t
and/or treat a bacterial infection or a disease caused by or associated therewith. In one
embodiment, composition bed herein is not used to prevent and/or treat S. aureus infection
or a disease caused by or associated with such infection. In another specific embodiment, a
composition described herein is not used to prevent and/or treat a bacterial infection of a wound
(e.g., an open wound such as an incision, a laceration, a penetration, an abrasion, or a burn).
In a specific embodiment, the disease to be treated and/or prevented by administration
of a composition bed herein is not a wound (e.g., an open wound such as an incision, a
laceration, a penetration, an abrasion, or a burn).
.5 Patient Populations
In certain embodiments, a composition described herein may be administered to a
naive subject, i.e., a subject that does not have a disease or infection. In one embodiment, a
composition described herein is administered to a naive subject that is at risk of acquiring a
disease or infection.
In one embodiment, a sNAG nanofiber composition described herein may be
administered to a patient who has been diagnosed with a disease or infection. In another
ment, a composition described herein may be stered to a patient who displays one
or more symptoms of a disease or infection. In certain embodiments, a patient is diagnosed with
a disease or infection prior to administration of a composition described herein
In certain embodiments, the compositions described herein are administered to
patients diagnosed with an infection. For example, the compositions described herein may be
administered to a patient when a pathogen (e.g., virus, fungi or yeast) is detected in a biological
sample taken from the t. In one embodiment, a biological sample is obtained from the site
or area to be treated by the itions described herein or an area to which the compositions
described herein are to be administered. In one embodiment, a swab is used to collect cells or
pus from the site of the ted infection to detect an infection. In another ment, a
fluid is aspirated from the ted site of an infection (e. g., a wound) to detect an infection. In
yet another embodiment, a tissue biopsy is performed to detect an infection. In an embodiment
where the suspected site of an infection is a wound, a wound culture may be performed to detect
an infection. In another ment, the biological sample is obtained from blood, urine,
sputum or feces of the patient. In some embodiments, a blood or a urine test may be performed
to detect an infection (e. g., when an ion is suspected to have spread into the blood or other
tissues/organs). In some embodiments, the collected sample (e.g., cells, tissues or fluid) is tested
using DNA detection methods such as PCR for presence of one or more types of bacteria. In
other embodiments, immunofluorescence is, serology, culture (e.g., blood agar e), or
any other test known and/or practiced in the art may be used for laboratory diagnosis of an
ion.
In other specific embodiments, the itions described herein may be
administered to a patient diagnosed with or ying one or more symptoms of a disease, e.g., a
cancer, an IBD, Crohn’s disease, dermatitis, psoriasis or an infection (e.g., viral, yeast or fungi
infection). In certain embodiments, a patient is diagnosed with a disease (e.g., one of the
diseases listed above) or displays one or more symptoms of a disease prior to administration of a
composition described herein. A disease may be diagnosed by any method known to a d
artisan, including evaluation of the patient’s symptoms and/or detection of a pathogen in a
biological sample of the patient (e.g., as described above). In one example, the compositidns
described herein may be administered to a t diagnosed with a e by a treating
physician or another medical professional. In another example, a patient may use the
compositions described herein upon detection of one or more symptoms of a disease.
In certain embodiments, a subject to be administered a composition described herein
is a subject with no or low level of expression of one or more defensin peptides or a
mutation/deletionin a gene or genes encoding one or more defensin peptides In some
embodiments, a subject to be administered a composition described hereinIS a subject with no or
low or altered level of expression of one or more (ii-defensins (e.g., DEFAl, DEFAlB, DEFA3,
DEFA4, DEFAS, DEFA6), one or more B-defensins (e.g., DEFBl, DEFB2, DEFB4,
DEFB103A,DEFB104A,DEFB105B,DEFB107B, DEFB108B,DEFB110, DEFB112,
DEFB114, DEFB118, DEFB119, DEFB123, DEFB124, DEFB125, DEFB126, DEFB127,
DEFB128, DEFBl29, 1, DEFBl36), and/or one or more 9-defensins (e.g., DEFTIP).
In some embodiment, a subject to be administered a composition described herein15 a t
with no or low or altered level of expression of one or more of DEFAl , DEFA3, DEFA4,
DEFAS, DEFBI, DEFB3, DEFBIO3A, DEFB104A, 8B, DEFB112, DEFB114,
DEFBl 18, DEFB119, DEFB123, DEFB124, 5, DEFBIZ6, DEFB128, DEFB129 and
DEFB131. In certain embodiments, a subject to be administered a composition bed herein
is a subject with no or low or d level of expression of one or more Toll receptors (e.g.,
TLRl TLRl 1, and/or
, TLR2, TLR3, TLR4, TLRS, TLR6, TLR7, TLR8, TLR9, TLRlO,
TLR12). In yet other embodiments, a subject to be administered a composition described herein
is a subject with no or low or altered level of expression of one or more of IL-1 , CEACAM3,
SPAGl 1, SIGIRR ike receptor), IRAKl, IRAK2, IRAK4, TBKl, TRAF6 and IKKi. In
some embodiments, a subject to be administered a ition described herein is a t with
no or low or altered level of expression of one or more of IRAK2, SIGIRR, TLRl, TLR2, TLR4,
TLR7, TLR8, TLRlO and TRAF6. A low level of expression of a gene is a level that is lower
(e.g., more than 1.25 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 6
fold, 7 fold, 8 fold, 9 fold, 10 fold lower) than the normal level of expression. An altered level of
expression of a gene is a level that differs (e.g., by more than 20%, 25%, 30%, 50%, 75%, 100%,
150%, 200%, 250%, 300%) from the normal level of expression. Wherein the l”
expression of one or more defensin genes is: (i) the average expression level known to be found
in subjects not displaying symptoms or not diagnosed with the disease or infection to be treated;
(ii) the average expression level detected in three, five, ten, twenty, twenty-five, fifty or more
ts not ying symptoms or not sed with the disease or infection to be treated;
and/or (iii) the level of expression ed in a t to be administered a composition
described herein before the onset of the disease or infection.
In certain embodiments, a ition described herein is stered to a patient
who has been diagnosed with a solid tumor cancer, such as bone and connective tissue sarcomas,
brain cancer, breast cancer, ovarian cancer, kidney cancer, pancreatic cancer, esophageal cancer,
stomach cancer, lung cancer (e. g., small cell lung cancer (SCLC), non-small cell lung cancer
(NSCLC), throat cancer, and elioma), liver cancer, and prostate cancer. In a specific
embodiment, a composition described herein is administered to a patient who has been diagnosed
with Kaposi’s sarcoma.
In n embodiments, a composition described herein is administered to a patient
who has been sed with a skin cancer, such as ma, basal cell carcinoma, and
us cell carcinoma.
In certain embodiments, a composition described herein is administered to a patient
who has (e.g., has been diagnosed with) inflammatory bowel disease (e.g., ulcerative colitis) or
displays one, two or more symptoms of inflammatory bowel disease.
In certain embodiments, a composition described herein is administered to a patient
who has (e.g., has been diagnosed with) s disease (e.g., ileal Crohn’s disease) or displays
one or more symptoms of Crohn’s disease.
In certain embodiments, a composition bed herein is administered to a patient
who has (e.g., has been diagnosed with) a disease caused by a virus or an infection associated
with a virus (such as any disease caused by a virus or an infection associated with a virus
described herein), e.g., the patient has been infected by respiratory syncytial virus (RSV),
influenza virus (influenza A virus, influenza B virus, or influenza C , human
metapneumovirus (HMPV), irus, parainfluenza virus, SARS Coronavirus, human
immunodeficiency virus (HIV), hepatitis virus (A, B, C), ebola virus, herpes simplex virus (e.g.,
HSV—1, HSV-2), a, variola major, and/or variola ’minor. In certain embodiments, a
composition described herein is administered to a patient who displays one, two or more
symptoms of a disease caused by a virus or an infection associated with a virus (such as any
e caused by a virus or an infection associated with a virus described herein).
In certain embodiments, a composition described herein is administered to a patient
who has (e.g., has been diagnosed with) a wound (e.g., an open wound such as an incision, a
tion, a penetration, an on, or a burn) that has been infected by a virus. In a specific
embodiment, a composition described herein is not adriiinistered to a patient who has been
diagnosed with a wound that has been infected by a virus.
In certain embodiments, a composition described herein is administered to a patient
who has (e.g., has been diagnosed with) a disease caused by a fiingus or an infection associated
with a fungus (any disease caused by a fungus or an infection associated with a fungus described
herein); e.g., the t has been infected by Blastomyces, Paracoccidiodes, Sporothrix,
Cryptococcus, Candida, Aspergillus, Histoplasma, Cryptococcus, Bipolaris, Cladophialophora,
Cladosporium, Drechslera, Exophiala, Fonsecaea, Phialophora, Xylohypha, Ochroconis,
Rhinocladiella, Scolecobasidium, and/or lla. In certain embodiments, a ition
described herein is administered to a patient who ys one, two or more symptoms of a
disease caused by a fungus or an infection associated with a fungus (such as any disease caused
by a virus or an infection associated with a fungus described herein).
In certain embodiments, a composition described herein is administered to a patient
who has (e.g., has been diagnosed with) a wound (e.g., an open wound such as an incision, a
laceration, a penetration, an abrasion, or a burn) that has been infected by a fungus. In a specific
embodiment, a ition described herein is not administered to a patient who has been
diagnosed with a wound that has been infected by a fungus.
In certain embodiments, a composition described herein1s administered to a patient
who has (eg., has been diagnosed with) a disease caused by a yeast or an infection associated
with a yeast, e.g., the patient has been infected by Aciculoconidium, Botryoascus,
Brettanomyces, Bullera, Bulleromyces, Candida, Citeromyces, Clavispora, Cryptococcus,
Cystofilobasidium, Debaromyces, Debaryomyces, Dekkera, scus, Endomyces,
Endomycopsis, Erythrobasidium, Fellomyces, Filobasidium, Guilliermondella, Hanseniaspora,
Hansenula, waea, Hyphopichia, Issatchenkia, Kloeckera, Kluyveromyces, Komagataella,
Leucosporidium, Lipomyces, Lodderomyces, Malasseiia - Mastigomyces, Metschnikowia,
, Nadsonia, Octosporomyces, Oosporidium, Pachysolen, Petasospora, , Pichia,
Pseudozyma, Rhodosporidium, Rhodotorula, Saccharomyces, romycodes,
romycopsis, Schizoblastosporion, Schizosaccharomyces, Schwanniomyces, Selenotila,
Sirobasidium, Sporidiobolus, Sporobolomyces, Stephanoascus, Sterigmatomyces, Syringospora,
spora, Torulopsis, Tremelloid, Trichosporon, Trigonopsis, Udeniomyces, Waltomyces,
Wickerhamia, Williopsis, Wingea, Yarrowia, Zygofabospora, Zygolipomyces, and/or
Zygosaccharomyces.
In certain embodiments, a composition described herein is administered to a patient
who has (e.g., has been diagnosed with) a wound (e.g., an open wound such as an incision, a
laceration, a penetration, an abrasion, or a burn) that has been infected by a yeast. In a specific
embodiment, a composition described herein is not administered to a patient who has been
sed with a wound that has been infected by a yeast.
In certain embodiments, a composition described herein is stered to a patient
who has (e. g., has been diagnosed with) a skin disease or displays one, two or more symptoms of
a skin disease. In a specific embodiment, a composition described herein is administered to a
patient who has been diagnosed with dermatitis (e.g., atopic dermatitis) or displays one, two or
more symptoms of dermatitis. In another specific embodiment, a composition described herein
is administered to a patient who has been diagnosed with psoriasis or displays one, two or more
symptoms of psoriasis.
In some embodiments, a composition described herein is administered to an
immunosuppressed patient, and/or a patient tible to acute or c disease or infection
(e.g., an HIV positive patient, or a patient suppressed as a result of cancer treatment or a
transplantation ure). In one embodiment, a composition described herein is administered
to a patient diagnosed with cystic fibrosis.
In some embodiments, a composition described herein is administered to a patient
with a disease or infection before ms of the disease or infection manifest or before
symptoms of the disease or infection become severe (e.g., before the t requires treatment or
hospitalization). In some embodiments, a ition described herein is stered to a
patient with a disease or ion afier symptoms of the disease or infection manifest or after
symptoms of the disease or infection become severe (e.g., after the patient es treatment or
alization).
In some embodiments, a subject to be administered a composition described herein is
an animal. In certain embodiments, the animal is a bird. In certain embodiments, the animal is a
. In certain embodiments, the animal is a feline. In certain embodiments, the animal is a
horse. In certain ments, the animal is a cow. In certain embodiments, the animal is a
mammal, e.g., a horse, swine, mouse, or primate, preferably a human.
2012/033782
In certain ments, a t to be administered a composition described herein
is a human adult. In certain ments, a subject to be administered a composition described
herein is a human adult more than 50 years old. In certain embodiments, a subject to be
administered a composition described herein is an elderly human subject.
In certain ments, a subject to be administered a composition described herein
is a human toddler. In certain ments, a subject to be administered a composition
described herein is a human child. In certain embodiments, a subject to be administered a
composition bed herein is a human infant. In certain embodiments, a subject to be
administered a composition described herein is a premature human infant.
In a specific embodiment, a composition described herein is not administered to a
subject to prevent and/or treat a bacterial ion or a disease caused by or associated therewith.
In one embodiment, a composition described herein is not administered to a subject to prevent
and/or treat S. aureus infection or a disease caused by or associated with such infection. In
another specific embodiment, a composition described herein is not administered to a subject to
prevent and/or treat a bacterial infection of a wound (e.g., an open wound such as an incision, a
laceration, a penetration, an abrasion, or a burn).
In a specific embodiment, a composition described herein is not administered to a
subject to treat a wound (e. g., an open wound such as an incision, a laceration, a penetration, an
abrasion, or a burn).
.6 Modes of Administration
In n embodiments, methods are bed herein for treating or preventing an
infection and/or a e or a symptom thereof, wherein a composition comprising the sNAG
nanofibers is topically administered to a patient in need of such treatment. In some
embodiments, a sNAG nanofiber composition is applied topically to tissue or organ which has an
increased risk of an ion or a disease.
In some embodiments, an effective amount of the sNAG nanofibers and/or a sNAG
nanofiber composition is administered to a subject.
In some embodiments, a composition comprising the sNAG nanofibers is
administered topically to the site of an infection or a disease in a patient or to the site ed by
an ion or a disease. In yet other embodiments, a composition comprising the sNAG
nanofibers is administered topically to the site and around the site of an infection or a disease in a
2012/033782
t or to the site affected by an infection or a disease. In yet other embodiments, a
composition comprising sNAG nanofibers is applied in proximity to the site of an infection or
disease in a patient or in proximity to the site affected by an infection or a disease. In yet another
embodiment, acomposition comprising the sNAG nanofibers is administered topically to the site
at high risk of an infection or a disease associated with such ion.
The sNAG nanofiber compositions described herein may be administered by any of
the many suitable means of topical administration which are well known to those skilled in the
art, including but not limited to topically to the skin, topically to any other surface of the body
(e. g., mucosal surface), by tion, intranasally, vaginally, rectally, buccally, or gually.
The mode of topical administration may vary depending upon the infection or disease to be
treated or ted. The sNAG nanofiber itions can be formulated for the s types
of topical administration.
In a specific ment, the compositions disclosed herein are applied lly, for
example to the skin of a patient in need of such treatment or to another tissue of a patient in need
of such treatment. In some embodiments, the compositions may be applied directly to the site of
a disease or infection and/or in the proximity to the site of a disease or infection. In some
embodiments, the compositions may be applied directly to a site where a disease or infection
might potentially develop (e.g., to an open wound).
In one embodiment, a composition comprising sNAG nanofibers is applied to the skin
of a patient. For example, such a composition may be applied topically to the skin of a patient
for treating or preventing a disease or infection of the skin.
In another embodiment, a composition described herein may be applied topically to a
mucosal surface of a t. For example, such a composition may be applied topically to the
oral mucosa for treating or ting a disease or infection of the mouth or guns.
In some embodiments, a composition described herein may be applied topically to a
genital, urinal or anal surface/area of a patient. For example, such a composition may be applied
topically to genital, urinal or anal surface/area for ng or preventing a l, urinal or anal
disease or infection.
The listed methods for topical administration may include administration of a
sNAG nanofiber in the form of a suspension (e.g., a thick suspension), a cream, an ointment, a
gel, a liquid solution, a membrane, a spray, a paste, a powder or any other formulation described
herein or known in the art. A sNAG nanofiber may also be applied in a ng or a bandage,
for example to treat localized diseases or infections on the skin of a patient. In particular
embodiments, compositions comprising sNAG nanoflbers are not solid or barrier-forming.
In some embodiments, a composition described herein may be applied as a spray into
the oral cavity and/or respiratory system of a patient. For example, such a composition may be
applied as a spray for treating or preventing a disease or infection of the mouth, nose, gums,
throat or lungs. In one such embodiment, the composition may be ated to be stered
as an inhaler.
In some embodiments, a composition described herein may be applied as a
suppository in the rectum, vagina or urethra of a t. For example, such ition may be
applied as a suppository for ng or preventing a e or infection of the digestive tract,
urinary tract or reproductive tract.
In some embodiments, a composition described herein may be applied topically with
a syringe or another type of applicator (e.g., a spatula, a cotton swab, a tube such as a squeeze
tube) suitable for topical delivery of the composition to the patient. For example, a composition
described herein formulated as a suspension (e.g., thick suspension), a liquid solution, a cream,
an ointment, or a gel can be administered topically to the skin, mucous membrane or other
surface tissue of a patient via an applicator (e.g., syringe).
In another embodiment, a composition described herein may be applied at the site of
a surgical procedure. For example, such composition may be sprayed, d as a cream,
suspension (e. g., a thick suspension), liquid solution, ointment, gel, ne, or powder, or
coated on the e of the tissue or organ to be subjected to a surgical procedure or that has
been subjected to the surgical procedure. In one embodiment, a composition described herein is
applied at the site of the surgical incision, at the site'ofthe excised , or at the site of surgical
stitches or s. Such administration of a composition described herein may prevent a post-
surgical infection or may prevent recurrence of a disease for which the surgery was ted.
For example, a composition described herein may be used during or after a surgical procedure
which is known to pose high risk of a viral, yeast, or fungal infection. Surgical procedures that
are known to pose high risk of an infection include bowel resection, gastrointestinal surgical
procedures, kidney y, etc. A composition described herein may be applied at the site of
any of the listed or other surgical procedures.
In yet other embodiments, a composition described herein may be coated on a device,
for example an oral hygiene product, a catheter, a surgical instrument or another product, to be
used in or inserted into a patient, in order to treat or prevent a disease or infection in a patient.
In a specific embodiment, the compositions disclosed herein are applied topically to
the site of a solid tumor or skin . In some embodiments, the itions are applied
directly to the solid tumor or skin cancer itself. In some embodiments, the compositions are
applied directly to the site of a solid tumor or skin cancer, wherein all or part of the tumor or skin
cancer has been removed (e.g., surgically removed). In some ments, the compositions
disclosed herein are topically administered to the site and/or around the site from which a solid
tumor or skin cancer has been excised or removed. In some of these embodiments, such
compositions may be sprayed, applied as a sion, liquid solution, cream, ointment, gel,
membrane, or powder, or‘coated on the surface of an organ or tissue from which a solid tumor
was excised. In c embodiments, the compositions described herein are sprayed or coated
at and around the site or sites of removed or excised solid tumor or skin cancer.
In some embodiments, methods contemplated herein include a step that es
detection/diagnosis of a disease or an infection in a patient. In some embodiments,
detection/diagnosis es a test or assay for one or more pathogen (e.g., a virus, a fungi, or an
yeast) in a biological sample of the patient. In other embodiments, diagnosis involves ing
whether the patient has one or more symptoms of a disease (e.g., IBD, Crohn’s disease, cancer,
dermatitis, sis, or a disease associated with a viral, fungal, or yeast infection).
The compositions bed herein may exhibit sustained release properties and/or
may be administered in a formulation resulting in a ned release of such compositions. In
some ments, the sNAG nanofibers biodegrade over time as described in Section 5.1,
release of
supra, and these properties of sNAG nanofibers may lead to or contribute to sustained
the compositions described herein. In yet other embodiments, the compositions described herein
are formulated to display sustained release capabilities using any methods known in the art. The
compositions described herein may exhibit sustained release over a time period equal to or more
than about 6 hours, 12 hours, 18 hours, 24 hours (1 day), 2 days, 3 days, 5 days, 7 days (1 week),
days, 14 days (2 weeks), 3 weeks or 4 weeks after administration of the composition to the
patient.
Contemplated treatment regimes include a single dose or a single application of a
sNAG nanofiber ition; two doses or two applications of a sNAG nanofiber ition;
or a regiment of multiple doses or multiple applications of a sNAG nanofiber composition. A
dose or an ation may be administered hourly, daily, weekly or monthly. For example, a
dose of a sNAG nanofiber composition may be administered once a day, twice a day, three times
a day, four times a day, once a week, 2 times a week, 3 times a week, every other day, once in 2
weeks, once in 3 weeks, once in 4 weeks, once a month, or once in two months.
A sNAG nanofiber composition may be administered for a duration equal to or
greater than 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3
months, 4 months, 5 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 4
years, 5 years, 7 years, 10 years or more. In some embodiments, a sNAG fiber composition is
administered to a t once or twice a day for a duration equal to or greater than 2 days, 3
days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5
months, 6 months, 9 , or 1 year. In one such embodiment, a sNAG nanofiber
composition does not cause any side effects or causes only mild side effects during the on
of the treatment. In another embodiment, a sNAG nanofiber composition does not cause
irritation (e. g., moderate or severe irritation) or allergy (e.g., moderate or severe allergy).
The concentration of sNAG nanofibers in a composition may vary. In general, an
effective amount of sNAG nanofibers are used in the compositions described herein to treat the
diseases described herein. An effective amount may be an amount sufficient to achieve one or
more of the effects bed herein, for example an amount effective to treat a disease or reduce
or ate one or more symptoms of a disease. For example, a composition may comprise
about 0.2 to 20 mg/cm2 of sNAG nanofibers per dose/application of the composition in a form
le for topical delivery to a patient. In certain embodiments, a composition described herein
comprises about 0.25 to 20 mg/cmz, about 0.5 to 20 mg/cmz, about 1 to 20 mg/cmz, about 1 to 15
mg/cmz, about 1 to 12 mg/cmz, about 1 to 10 mg/cmz, about 1 to 8 mg/cmz, about 1 to 5 mg/cmz,
about 2 to 8 , or about 2 to 6 mg/cm2 of sNAG nanofibers per dose/application of the
composition in a form suitable for topical delivery to a t. In some embodiments,
compositions described herein can comprise about 5 to 50 mg/ml of sNAG nanofibers per
dose/application of the ition in a form suitable for l delivery to a t. In certain
embodiments, a composition described herein comprises about 5 to 40 mg/ml, about 5 to 35
mg/ml, about 10 to 50 mg/ml, about 10 to 40 mg/ml, about 10 to 35 mg/ml, about 10 to 30
mg/ml, about 15 to 40 mg/ml, about 15 to 35 mg/ml, about 15 to 30 mg/ml, or about 20 to 30
mg/ml of sNAG nanofibers per dose/application of the composition in a form suitable for l
delivery to a patient. In specific embodiments, a composition described herein comprises about
mg/ml, 12 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml or_ 30 mg/ml of sNAG nanofibers per
dose/application of the composition in a form suitable for topical delivery to a patient. In certain
embodiments, compositions described herein can comprise an amount of total solution or
suspension (comprising sNAG nanofibers) in the range of about 50 to 100 pl, 50 to 200 pl, 50 to
250 pl, 50 to 300 pl, 50 to 350 pl, 50 to 400 pl, 50 to 450 pl, 50 to 500 pl, 100 to 200 pl, 100 to
300 pl, 100 to 400 pl, 100 to 500 pl per 0.5 cm2 or 1 cm2 of the surface to be treated in a patient
(e.g., skin, mucosal surface or other tissue surface). The total solution or suspension can
comprise saline, buffer, solution (e. g., Hank buffer on), or any other physiologically
compatible solution.
.7 ation Therapy
In various ments, the sNAG nanofibers bed herein or itions
thereof may be administered to a subject in ation with one or more other ies. The
one or more other therapies may be beneficial in the treatment or prevention of a disease or may
ameliorate a symptom or condition associated with a disease. In certain embodiments, the
therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at
about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at
about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to
about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours
apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about
hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to
18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart,
48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84
hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In specific embodiments,
two or more therapies are administered within the same patent visit.
In certain embodiments, the one or more therapies is surgery. In a specific
embodiment, surgery is performed to remove all or part of a solid tumor or skin cancer, and a
composition described herein is administered to the site of the tumor before, during, and/or after
the surgery. In certain ments, the one or more therapies is radiation therapy.
] In certain embodiments, the one or more therapies is an iral agent. Any anti-
viral agents well-known to one of skill in the art may used in combination with the sNAG
nanofibers described herein or compositions thereof. miting examples of anti-viral agents
include proteins, polypeptides, peptides, fusion proteins antibodies, nucleic acid molecules,
organic molecules, inorganic molecules, and small molecules that inhibit and/or reduce the
attachment of a virus to its receptor, the internalization of a virus into a cell, the replication of a
virus, or release of virus from a cell. In particular, anti-viral agents include, but are not limited
to, nucleoside s (e.g., zidovudine, acyclovir, gangcyclovir, vidarabine, idoxuridine,
trifluridine, and ribavirin), foscamet, amantadine, peramivir, adine, saquinavir, vir,
ritonavir, alpha-interferons and other interferons, AZT, zanamivir za®), and oseltamivir
- (Tamiflu®). Other anti-viral agents include influenza virus vaccines, e.g., Fluarix®
SmithKline), FluMist® (MedImmune Vaccines), Fluvirin® (Chiron Corporation),
Flulaval® (GlaxoSmithKline), Afluria® (CSL Biotherapies Inc.), ® (Novartis) or
Fluzone® (Aventis Pasteur).
In certain embodiments, the one or more therapies is an anti-cancer agent. In a
specific embodiment, the anti-cancer agent is a chemotherapeutic agent. Any ancer agents
known to one of skill in the art may used in combination with the sNAG nanofibers described
herein or compositions thereof. Exemplary anti-cancer agents include: acivicin; anthracyclin;
anthramycin; azacitidine (Vidaza); bisphosphonates (e.g., pamidronate (Aredria), sodium
clondronate (Bonefos), zoledronic acid (Zometa), alendronate (Fosamax), etidronate,
rnate, cimadronate, risedromate, and tiludromate); latin; chlorambucil; tin;
cytarabine (Ara-C); daunorubicin hloride; decitabine (Dacogen); demethylation agents,
docetaxel; doxorubicin; EphA2 inhibitors; etoposide; fazarabine; fluorouracil; gemcitabine;
histone deacetylase inhibitors (HDACs); interleukin 11 (including recombinant interleukin II, or
rIL2), interferon alpha; interferon beta; interferon gamma; lenalidomide (Revlimid); anti-CD2
antibodies (e.g., siplizumab mmune Inc.; International Publication No. W0 02/098370,
which is incorporated herein by reference in its ty»; melphalan; methotrexate; mitomycin;
oxaliplatin; paclitaxel; puromycin; riboprine; spiroplatin; tegafur; teniposide; vinblastine sulfate;
vincristine e; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
Other examples of cancer therapies include, but are not limited to angiogenesis
inhibitors; antisense oligonucleotides; apoptosis gene modulators; apoptosis regulators;
L antagonists; beta lactam derivatives; casein kinase inhibitors (ICOS); estrogen
agonists; estrogen antagonists; glutathione inhibitors; HMG CoA reductase inhibitors;
immunostimulant peptides; insulin-like growth factor-1 receptor tor; interferon agonists;
interferons; interleukins; lipophilic platinum compounds; matrilysin inhibitors; matrix
metalloproteinase inhibitors; mismatched double stranded RNA; nitric oxide modulators;
oligonucleotides; platinum compounds; protein kinase C inhibitors, protein tyrosine phosphatase
inhibitors; purine nucleoside orylase inhibitors;'raf antagonists; signal uction
inhibitors; signal transduction modulators; translation inhibitors; tyrosine kinase inhibitors; and
urokinase receptor antagonists.
In some embodiments, the therapy(ies) used in combination with the sNAG
nanofibers described herein or compositions thereof is an anti-angiogenic agent. Non-limiting
examples of anti-angiogenic agents include proteins, polypeptides, peptides, ates,
antibodies (e.g., human, humanized, chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab
fragments, F(ab)2 fragments, and antigen-binding fragments thereof) such as antibodies that
specifically bind to TNF-a, nucleic acid les (e.g., antisense les or triple helices),
organic les, inorganic molecules, and small molecules that reduce or inhibit angiogenesis.
Other examples of anti-angiogenic agents can be found, e.g., in US. ation No.
2005/0002934 A1 at paragraphs 2, which is incorporated by reference in its entirety. In
other embodiments, the therapy(ies) used in accordance‘with the invention is not an anti-
angiogenic agent.
In some embodiments, the therapy(ies) used in ation with the sNAG
nanofibers described herein or compositions thereof is an anti-inflammatory agent. miting
examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs s)
(e.g., celecoxib (CELEBREXTM), diclofenac (VOLTARENTM), etodolac (LODINETM),
fenoprofen (NALFONTM), indomethacin (INDOCINTM); lac (TORADOLTM), oxaprozin
(DAYPROTM), nabumentone (RELAFENTM), sulindac RILTM), tolmentin
(TOLECTINTM), rofecoxib (VIOXXTM), en (ALEVETM, NAPROSYNTM), ketoprofen
(ACTRONTM) and nabumetone (RELAFENTM)), steroidal anti-inflammatory drugs (e.g.,
orticoids, dexamethasone (DECADRONTM), corticosteroids (e.g., methylprednisolone
(MEDROLTM)), cortisone, hydrocortisone, prednisone ISONETM and DELTASONETM),
and prednisolone (PRELONETM and PEDIAPREDTM», anticholinergics (e.g., atropine sulfate,
atropine methylnitrate, and ipratropium bromide ENTTMD, agonists (e.g.,
abuterol (VENTOLIN'rM and PROVENTILTM), bitolterol (TORNALATETM), levalbuterol
(XOPONEXTM), metaproterenol (ALUPENTTM), pirbuterol (MAXAIRTM), terbutlaine
(BRETHAIRETM and BRETHINETM), albuterol NTILTM, REPETABSTM, and
VOLMAXTM), formoterol (FORADIL AEROLIZERTM), and salmeterol (SEREVENTTM and
SEREVENT DISKUSTM)), and methylxanthines (e.g., theophylline YLTM, THEO-
DURTM, SLO-BIDTM, AND TEHO-42TM)).
In certain ments, the therapy(ies) used in combination with the sNAG
nanofibers bed herein or compositions thereof is an ting agent, a nitrosourea, an
antimetabolite, an anthracyclin, a topoisomerase II inhibitor, or a mitotic inhibitor. Alkylating
agents include, but are not limited to, busulfan, cisplatin, carboplatin, cholormbucil,
cyclophosphamide, ifosfamide, decarbazine, rethamine, mephalen, and themozolomide.
Nitrosoureas include, but are not limited to cannustine (BCNU) and lomustine (CCNU).
Antimetabolites include but are not limited to S-fluorouracil, capecitabine, methotrexate,
gemcitabine, cytarabine, and fludarabine. Anthracyclins e but are not limited to
daunorubicin, doxorubicin, epirubicin, idarubicin, and mitoxantrone. Topoisomerase II
inhibitors include, but are not limited to, topotecan, irinotecan, etopiside (VP-16), and teniposide.
Mitotic inhibitors include, but are not limited to taxanes (paclitaxel, docetaxel), and the vinca
alkaloids (vinblastine, vincristine, and vinorelbine).
In some embodiments, the therapy(ies) used in combination with the sNAG
nanofibers described herein or compositions thereof is an anti-pain medication (e.g., an
analgesic). In some embodiments, the therapy(ies) used in combination with the sNAG
ers described herein or itions thereof is an anti-fever medication.
.3 fl
Also provided herein is a pharmaceutical pack or kit comprising one or more of the
sNAG nanofiber compositions described herein. The pack or kit may comprise one or more
containers filled with one or more ingredients comprising the compositions described .
The composition is preferably contained within a sealed, water proof, sterile package which
facilitates removal of the ition without ination. Materials from which containers
may be made include um foil, plastic, or another conventional material that is easily
ized. The kit can contain material for a single administration or for multiple administrations
of the composition, preferably wherein the material for each administration is provided in a
separate, waterproof, e package.
In another embodiment, a container having dual compartments is provided. A first
compartment contains any of the described sNAG nanofiber compositions described
herein, while the second compartment contains another active agent such as another agent to be
used in combination with the sNAG nanofiber composition. In the field or the clinic, the
composition in the first compartment can be readily combined with the agent in the second
compartment for subsequent stration to a patient.
The kit can also contain an applicator for administration of one or more of the sNAG
nanofiber compositions described herein, and/or for administration of another active agent such
as r agent to be used in combination with the sNAG nanofiber composition. In .one
embodiment, the kit comprises an applicator for topical administration of a sNAG nanofiber
composition. Examples of ators for l administration of a sNAG nanofiber
ition include, without limitation, a syringe, a spatula, a tube (a squeeze tube), and a
cotton swab.
Additionally, a kit designed for emergency or military use can also contain disposable
pre-sterilized instruments, such as scissors, scalpel, clamp, quet, elastic or inelastic
bandages, or the like.
Optionally associated with such kit or pack can be a notice in the form prescribed by
a governmental agency regulating the manufacture, use-[or sale of pharmaceuticals or biological
products, which notice reflects approval by the agency of manufacture, use or sale for human
administration. For example, a kit can se a notice regarding FDA approval and/or
instructions for use.
The kits encompassed herein can be used in the above applications and methods.
6. EXAMPLES
6.1 Example 1: sNAG Nanofibers From a Marine Diatom e Wound Healing and
Defensin Expression via an Aktl/Etsl-Dependent Pathway
This example demonstrates that sNAG nanofibers promote cutaneous wound healing
and expression of defensins, and that the Aktl—>Etsl pathway plays a central role in the
regulation of cutaneous wound healing by sNAG nanofibers.
6.1.1 als and Methods
sNAG nanofibers (in particular, Taliderm) are produced and supplied by Marine
Polymer Technologies and formed into suitable patches for wound treatment. Wildtype C57
Black and Aktl null mice were housed at the l University of South Carolina animal
facilities. Wildtype and Aktl null mice, ages ranging from eight to 12 weeks, were anesthetized
with 50% pure oxygen and 50% isoflurane gas. Immediately before wounding, Nair Hair
Removal Lotion was applied to their dorsum to remove any unwanted hair. A dorsal 4mm
circular area of skin was removed using an excision biopsy punch. rm was placed onto
each wound at day 0 or wounds were left untreated. At days 1,3,5, and 7-the wounds were
photographed, measured, and excised using an 8 mm biopsy punch to ensure complete l
of the wound and surrounding skin. Wildtype and Aktl null wounds with and without Taliderm
treatment were ed in paraffin in preparation for H&E and immunofluorescent staining.
Paraffin-embedded sections were sectioned and placed on microscope slides for
staining. Slides were washed with xylenes to remove n and rehydrated through a series of
graded alcohols. The sections were then incubated in 0.1% Triton x100 for permeabilization.
Sections were incubated in a boiling Antigen Retrival solution. 1% Animal serum was used for
blocking before incubating in the primary goat antibody, B-defensin 3 1:400 on. The
sections were then incubated in the primary antibody overnight at 4° in a humidity chamber. An
immunofluorescent secondary Donkey a-goat 488 antibody 1:200 dilution was used, followed by
r staining with TOPRO-3. Images were ed using confocal microscopy.
xylin and eosin staining was used towvisualize basic structures such as the
epidermis, dermis, muscle, and blood vessels and to determine the orientation and approximate
location in the wound. H&E staining was also used to begin to identify which cell types are
stimulated by Taliderm in an Aktl-independent manner.
Other materials and methods are described in figure descriptions and in the results
section below, and performed in accordance with the methods known in the art.
6.1.2 Results
] sNAG ers stimulate Akt 1 tion, an upstream regulator ofEtsl . Figure
1A shows a Western blot analysis of phospho-Akt in reSponse to NAG and sNAG stimulation of
serum d EC. Figure 1B shows RT-PCR analysis of EC infected either with led
control or Aktl shRNA lentiviruses and ed for sion of Etsl and $26 as a loading
control. Figure 1C illustrates a signal transduction pathway transducing a signal from sNAG
nanofibers to Aktl, Etsl and Defensins.
Delayed wound healing in Aktl null animals is lly d by Taliderm (sNA G)
treatment. Figure 2A shows representative images of wounded WT and AKTl null mice with
and without treatment of Taliderm. Figure 2B shows H&E staining of representative mouse
skin sections from day 3 wounds. H&E staining of wildtype and Aktl wound exicisons indicate
a Taliderm depdendent increase in keratinocyte proliferation and migration. The dashed lines
indicate the area of keratinocyte proliferation across the wound margin. In both the wildtype and
Aktl treated wounds there is an an evident increase in reepithelization across the wound margin
compared to the wildytpe and Aktl control. This indicates that Taliderm increases noctye
recruitment indepdent of the Aktl y. Although Taliderm induces a complete
reepithlization of the epidermis across the wound margin, there is still nial lack of
revascularization in the underlying tissue compared to the wildtype. This is evident by
substantial hemorrhaging and infiltration of red blood cells in the Aktl aminals.
sNAG nanofibers stimulate cytokine and defensirt expression in primary endothelial
cells. Figure 3A shows irnrnunohistochemisty of EC treated with or without sNAG using an
dy directed against a-defensin. Figure 38 presents ELISA showing that nanofiber
treatment of EC results in the secretion of a-defensins 1-3.
sNAG nanofibers stimulate defensin expression in primary endothelial cells in an
AktI dependent manner. Figures 4A and 4B show tative RT-PCR analyses of serum
starved EC treated with or without sNAG, with or without PD98059 (MAPK inhibitor),
Wortmannin (PI3K inhibitor) or infected with a scrambled control or Aktl shRNA lentiviruses
and assessed for expression of the genes indicated.
sNAG ers stimulate fl-defensin 3 expression in mouse keratinocytes. Figure
5A shows immunofluorescent staining with B-defensin 3 and Involucrin antibodies of paraffin
embedded mouse cutaneous wound sections from WT and Aktl null animals on Day 3. A
cutaneous wound healing model was developed in both WT and Aktl null mice to assess the
s of Taliderm in vivo. These findings show that B-defensin 3 expression increases in
Taliderm treated animals in an Aktl-dependent manner. The ability of Taliderm to increase
defensin expression in a healing wound has ant implications for treating and controlling
wound infection. Figure 5B shows quantification of B—defensin 3 immunofluorescent ng
using NIHImageJ sofiware. Figure 5C shows imrnunofluorescent staining ofWT and Aktl null
treated and untreated keratinocytes with B-Defensin 3 and TOPRO-3. Notice the increase in
green B-Defensin 3 staining in WT and Aktl rm treated wounds. The immunofluorescent
labeling of wound sections illustrates that Taliderm treated wounds show an increase in B-
defensin 3 expression in an Aktl dependent manner. Although the Aktl treated wounds show a
reasonable increase in nsin 3, the wildtype treated wounds illustrate a more remarkable
increase. This tes that B-defensin 3 expression is not only increased by application of the
nanofiber, but is at least partially dependent on the Aktl pathway. B-defensin 3 sion seems
limited to the keratinocytes ting this expression is keratinocyte specific.
Aktl dependent transcriptionfactor binding sites. Figure 6 shows tic of Aktl
ent transcription factor binding sites. Using Genomatix sofiware, 500 bp upstream of the
transcription start site was analyzed for conserved sites on the mRNA of DEF], 4, and 5.
6.1.3 Conclusions
The provided data show that sNAG er stimulation of Etsl results from the
activation of Aktl by these nanofibers. Nanofiber treatment resulted in marked ses in the
expression of genes involved in cellular recruitment, such as IL-1 (3 known Etsl target), VEGF
and several defensins (B3, (11, a4, and (15), small anti-microbial peptides recently shown to act as
chemoattractants. Both pharmacological inhibition of the PI3K/Akt1 pathway and Aktl
knockdown using shRNAs resulted in decreased sion of these chemotactic factors. Aktl
null mice exhibited a delayed wound healing phenotype that is partially rescued by Taliderm
nanofibers. Taliderm treated wounds also showed an increase in in expression that is Aktl
dependent.
The se of B-defensin 3 sion and nocyte proliferation in Taliderm
treated wounds demonstrates the beneficial use of Taliderm as an effective wound healing
product. rm acts to increase anti-microbial peptide expression in keratinocytes in an Aktl
dependent manner suggesting the essential role of Aktl in the on of sNAG nanofibers.
This correlates with the results from other studies in the laboratory (Buff, Muise-Helmericks,
unpublished) that inhibition of the PI3K/Akt1 pathway and Aktl own using shRNAs
results in sed expression of these chemotactic factors.
Although the increased sion of B—defensin 3 is Aktl-dependent, H&E
staining of 8 mm wound excisions (Figure 2B) indicated that Taliderm acts independent of Aktl
in wound reepithelization. Even though the new keratinocytes span the entire wound margin, the
underlying tissue did not demonstrate the same stimulation in vascular growth. This indicates
the that absence of Aktl is responsible for leaky blood vessels and the large amount of g
red blood cells in the dermis. This suggests that Taliderm is dependent on the Aktl pathway for
an increase in vascularization.
In summary, (i) sNAG nanofibers (such as rm) se wound healing in part
by stimulating angiogenesis; (ii) sNAG nanofibers treatment of endothelial cells activate an
Aktl/Etsl dependent pathway leading to changes in cell motility and cytokine secretion; (iii)
Taliderm treated wounds show increased expression of B-defensin 3 in an AKTl dependent
manner; (iv) treatment of Aktl null animals with Taliderm partially rescues the ype,
leading to markedly increased keratinocyte eration/migration; and (v) bioinformatics
analysis indicates that ETSl is likely involved in the sNAG activated pathway leading to
increased wound healing and cytokine secretion.
Taken together these findings suggest a central role of the Aktl—)Etsl y in the
regulation of cutaneous wound healing by sNAG nanofibers and support the use of these
nanofibers as a novel and effective method for enhancing wound healing.
6.2 Example 2: sNAG Nanofibers IncreaseuDefensin Expression, Increase Kinetics of
Wound Closure, and Have an Indirect Defensin-Dependent acterial Effect.
This example demonstrates that sNAG nanofibers have a potent anti-bacterial effect
against Staphylococcus aureus in vivo, which is indirect and defensin-dependent. This example
also shows that sNAG nanofibers induce expression of defensins in vitro in keratinocytes and
endothelial cells and in vivo in cutaneous wounds, in an Akt-l dependent , and increase
the kinetics of wound closure.
6.2.1 Materials and s
Tissue Culture, Pharmacological Inhibition, ELISA: Human umbilical cord vein EC
(Lonza) were maintained at 37° with 5% C02 in endothelial basal medium 2 (Lonza).
Endothelial basal medium 2 (EBM2) was supplemented with EC growth medium 2 SingleQuots
as described by Lonza procedures .and 1% penicillin/streptomycin (Invitrogen). Serum tion
was performed at 80-90% confluency in EBM2 supplemented with 0.1% fetal calf serum 01alley
Biomedical) for 24 hours followed by stimulation with highly d pGlcNAc (50ug/ml)
nanofibers (sNAG) in sterile water ded by Marine Polymer Technologies, Inc., Danvers,
Mass, USA). The pGlcNAc diatom-derived nanofibers used in this study are short
biodegradable fibers d from a longer form (NAG), and have an average length of 4-7pm
and a polymer molecular weight of approximately 60,000Da. For inhibition using PD098059
(SOuM) or wortmannin (lOOnM), cells were pre-treated for 45 minutes prior to 3 hour
stimulation with sNAG (50ug/ml).
Statistical Analysis: Each tative experiment was performed at least in triplicate
at least three independent times. All statistical analyses were performed using Microsoft Excel to
calculate means, standard deviations and t t-test
Lentiviral Infection: Mission shRNA lentiviral constructs directed against Aktl were
purchased from Sigma/Aldrich. A scrambled pLKOil shRNA vector was sed from
Addgene. Lentiviruses were propagated in 293T cells, maintained in DMEM supplemented as
above. Lentiviral production was performed using psPAXZ and pMD2.G packaging vectors
sed from Addgene using the protocol for producing lentiviral particles from Addgene. For
infection of target cells, 7.5 X 105 cells were plated on 100 mm2 plates and allowed to incubate
overnight. The next day, cells were transduced using a final concentration of 1 ug/ml polybrene
and either scrambled control or Aktl shRNA lentiviruses. After uction, endothelial cells
were serum starved overnight and stimulated with sNAG (50g/ml) for 3 hours. All infections
were monitored for riate knockdown by .
: For semi-quantitative RT-PCR, RNA was extracted with RNAsol (Teltest,
Inc.) following manufacturer’s instructions. cDNA was synthesized from 2 ug total RNA with a
Superscript First Strand Synthesis Kit (Invitrogen), using Oligo(dT) following the
manufacturer’s instructions. PCR reactions contained equal amounts ofcDNA and 1.25 [AM of
the appropriate primer pair (Sigma- Proligo, St. Louis, MO, USA). All primer sequences used in
these es are as follows:
Cycling conditions were: 94°C for 5 min; 30-35 cycles of 94°C for l min, C
(based on primer Tm) for 1 min, 72°C for 1 min; 72°C for 7 min and cooled to 4°C. Cycle
number was empirically determined to be within the linear range of the assay for each primer
pair used. All uantitative RT-PCR was performed with the ribosomal protein subunit $26
primers as internal controls. Products were visualized on a BioRad Molecular Imaging System
(Hercules, CA, USA). Real time PCR was med using a Brilliant CYBR green QPCR kit in
combination with an P Real-Time PCR system both purchased from Stratagene. Primers
detecting the ribosomal subunit 826 were used as internal controls.
Excisional Wound Healing Model: Wild Type C57Bl/6 and Aktl—l- [43] were used in
all experiments. The Aktl null animals were created using an insertional nesis strategy at
the translational start site that blocks expression of the entire protein. ng was performed
on anesthetized adult male mice between 8-12 weeks old. Two full thickness cutaneous wounds
were created using a 4mm biopsy punch (Miltex), to create two identical wounds on each flank.
Mice were anesthetized using an 02/Isoflurane vaporiziiig anesthesia machine (VetEquip, Inc.).
Isoflurane was used at 4% for induction; 2% for y. Prior to surgery hair was removed by
depilation and the area was washed and sterilized using 70% ethanol. Wounds were either treated
with sNAG membrane moistened with distilled water or left untreated. On days 3 and 5 animals
were euthanized and entire wounds were harvested including the surrounding skin using an 8
mm biopsy punch (Miltex). Wounds were fixed in 4% rrnaldehyde overnight at 4°,
embedded in paraffin, and sectioned for analysis.
Hematoxylin and Eosin Staining (H&E): All H&E staining was performed in the
Histology Core Facility at the Medical University of South Carolina, Department of
Regenerative Medicine and Cell Biology. Briefly, sections were cleared in xylene, rehydrated
through a series of graded alcohols, placed in Hematoxylin followed by acid l. Samples
were then placed in ammonia water, rinsed in ethanol and exposed to Eosin before dehydrating
h graded alcohols and clearing in xylene. Sections were mounted using Cytoseal-XYL
(Richard-Allan Scientific). H&E ns were ized using an Olympus BX40 microscope
(4x objective lens, 0.13) and captured using an Olympus Camera (Model DP25) and DPZ-BSW
ition software.
Bacterial Inoculation, Tissue Gram Staining, Colony Farming Unit Quantitation:
Male mice n 8-12 weeks were wounded as described above. Single colonies of
Staphylococcus aureus (ATCC 25923) were picked and cultured overnight at 37° and adjusted to
an absorbance of OD500= 0.53. One mL of S. aureus was spun at 10,000rpm, re-suspended in
sterile PBS, and 15p] was used to innoculate each wound. sNAG nes were applied to the
treated group thirty minutes post inoculation. Mice were euthanized on day 3 and 5 post
wounding and wounds were ted using an 8 mm biopsy punch. One wound per animal was
fixed overnight in 4% paraformaldehyde at 4°C and the other wound was cultured and plated on
LB media without antibiotic for bacterial quantitation (see below). Wounds for tissue gram
staining were embedded in paraffin and sectioned. Sections were cleared in xylene and
ated through a series of alcohol and were stained using a tissue gram stain -
Aldrich) by procedures described by the manufacturer.
For culturing, wound ns were placed in 0.5m] bacterial media an incubated for
min at 370C while shaking. Colony forming units (CFU) were tated using a dilution
series plated overnight at 37°C. Number of colonies per plate/per dilution were counted and
CFU/ml were calculated.
To determine CFU/ml from sNAG treated bacterial cultures, S. aureus cultures in
solution were treated with varying concentrations of sNAG (lOul and 20 ul of 10.8 mg/ml
sNAG) for three hours. Cultures were then plated overnight at 37° and CFU/ml were determined.
ensin 3 Peptide Application: Three test concentrations (1.0uM, 2.5uM, 5.0uM)
of biologically active human B—defensin 3 peptide (Peptide Institute, Inc.) were tested for their
effect on bacterial growth in the infected wound healing'model described above. Each
concentration negatively affected bacterial growth so the lowest concentration was chosen for
analyses. After each wound was ed with S. aureus, lOul of peptide was applied. Afier three
days, wounds were harvested, embedded for sectioning and gram staining, or cultured for
CFU/ml tation as described above.
,B-defensin 3 Antiboafiv de: Wild Type male mice were wounded and infected
with 15ul of S. aureus as bed above. After inoculation, one wound was treated with
0.2ug/mL of B-defensin 3 antibody (Santa Cruz) while the other was treated with 0.2ug/mL of
normal goat IgG control antibody (Santz Cruz). sNAG membranes were applied to all mice after
antibody ent on day 0. Antibody was applied every 24 hours. Mice were euthanized on day
3 and wounds were harvested using an 8 mm biopsy punch. Wounds were fixed overnight in 4%
paraformaldehyde at 4°C, ed in paraffin, sectioned, and analyzed using tissue gram stain.
CFU/ml quantitation was performed from wounds ted on day 3 as described above.
Immunofluoresence, Microscopy: Paraffin embedded tissue sections were re-
hydrated through xylene and a series of graded alcohols. Sections were d with 0.01%
Triton-X100 and subjected to antigen retrieval using antigen unmasking solution (Vector
Laboratories) in a pressure cooker for 5min and allowed to cool. Skin sections were labeled with
[3-defensin 3 goat polyclonal antibody (Santa Cruz), involucrin rabbit polyclonal antibody (Santa
Cruz), and TO-PRO 3-iodide (Molecular Probes). Sections were incubated in primary antibody
ght at 4° and appropriate secondary immunofluorescent antibodies (Invitrogen) for 1 hour
at room temperature. Control sections for each dy were stained without y antibody.
Tissue sections were visualized using an s FluroView laser scanning confocal
microscope (Model 1X70) and captured at ambient temperature using an Olympus camera
(Model FVS-ZM) and Fluoview 5.0 acquisition software. All tissue sections were imaged using
60x oil immersion lens (Olympus Immersion Oil)
HUVECs were either serum starved or treated with sNAG for 5 hours in culture and
stained with antibodies directed against (it-defensin 5 (FITC), B-defensin 3 (Texas Red), or
TOPRO 3 (Blue). Images were taken using immunofluorescent copy. Cell culture
in expression was visualized using a Zeiss Axiovert 100M confocal microscope and was
captured at ambient temperature, using water as the medium, using LSM 510 camera (Zeiss
Fluor 63xW/l .2A objective).
Western Blot Analysis: Endothelial cells were serum starved prior to stimulation with
SNAG (Soul/ml) for a given time course. Cells were then lysed and subjected to Western blot
analysis. The antibodies used for Western blot analysis are as follows: anti-p85 subunit of PI3K
and phosphospecific Akt antibody (Cell Signaling logies).
6.2.2 s
6.2.2.1. Keratinocytes and Endothelial Cells Express and Secrete Defensins
When Stimulated With SNAG
This example demonstrates that sNAG treatment modulates the expression of
defensins, small anti-microbial peptides that are part of the innate immune response.
To investigate the affect of SNAG treatment on defensin expression in vitro, primary
human umbilical vein endothelial cells in culture were used. Endothelial cells express both a-
type and B-type ins when stimulated with sNAG.‘ As shown in Figure 7A elial
cells treated with SNAG show an up-regulation of B-defensin 3 and a-defensin 1 mRNA
expression within 1 hour of stimulation. Similar up-regulation of a-defensin 4 and 5 by SNAG
treatment was also observed (data not shown). Custom gene arrays containing over 25 different
defensin genes were used to confirm the expression of the a-type defensins in primary
endothelial cells and the B-type defensins in nocytes. sNAG ation of endothelial
cells was shown to increase the expression specifically of a-defensins l, 4 and 5 and B-defensin
3. Additionally, SNAG ation of human keratinocytes sed sion of B-defensin
like genes, several of which are listed in Table 1. These s suggest that at least three 0.-
defensin genes and B-defensin 3 are expressed in primary endothelial cells and multiple B-
defensin genes are expressed in primary keratinocytes in response to sNAG stimulation.
Table I: Gene array analysis reveals numerous in genes upregulated by SNAG
Fold
HUVEC Gene Name Keratinocyte Gene Name Fold Change
Change
a-defensin 1 +1.36 B-defensin 1 +1.4
a-defensin 4 +2.74 B-defensin 126 +1.73
a-defensin 5 +2.46 B-defensin 105B +2.55
B-defensin 1 +2.19 B-defensin 123 +1.65
B-defensin 4 +3.06 B-defensin 129 +1.46
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To test r the sNAG-dependent defensin expression also occurred on the
protein level, sNAG stimulated endothelial cells were subjected to immunofluorescence using
antibodies directed against both a and B defensins. As shown in Figure 7B, both B—defensin 3
and a- defensin 5 are up-regulated upon sNAG ation in this cell type. However,
stimulation of primary human keratinocytes (HaCat) with sNAG did not cause increased
expression of a- defensin but does cause an se in the sion of B-defensin 3 (Figure
7C). Taken together, these experiments suggest that sNAG stimulation results in an up-
regulation of defensin peptides in both y keratinocytes and primary endothelial cells.
6.2.2.2. sNA G-Dependent Defensin Expression Requires Aktl
Previously published data show that sNAG stimulation of primary endothelial cells
results in increased integrin activation, Etsl expression and MAP kinase activation. (Vournakis,
J.N., et al., 2008, J Vasc Res. 222-32.) Findings position Aktl upstream of Etsl in
endothelial cells and in Drosophila. (Lavenburg, K.R., et al., 2003, FASEB J.17(15): 0.)
To begin to determine the signaling pathway responsible for the expression of defensins,
endothelial cells were serum starved and pre-treated with pharmacological inhibitors directed
against PI3K (wortrnannin) or MAP kinase (PD098059) prior to sNAG ation. Quantitative
real time PCR analysis shows that u-defensin 1 mRNA levels are greatly shed afier
inhibition of either the PIBK/Akt pathway or the MAP kinase pathway (Figure 8A). RT-PCR
analysis of B-defensin 3 also shows that levels are decreased by the inhibition of these pathways
as well (Figure 8B). sNAG treatment of elial cells for a short time course leads to
phosphorylation of Aktl, a rd indicator of its activation (Figure 8C). To confirm that
Aktl is indeed required for defensin expression, lentiviral delivery of shRNA directed against
Aktl was used. Quantitative RT-PCR of serum starved endothelial cells infected with scrambled
(SCR) control or Aktl shRNA followed with sNAG treatment confirms that Aktl expression is
required for sNAG-dependent (it-defensin expression (Figure 8D). Since B-defensins are known
to be expressed in epithelial cells, lentiviral delivery of shRNA directed against Aktl was used in
human keratinocytes (HaCat). sNAG treatment of serum starved keratinocytes infected with
led (SCR) control leads to a significant increase in B-defensin 3 expression that is
abrogated by Aktl knockdown (Figure 8E). These results rate that sNAG treatment
activates Aktl in endothelial cells and strongly suggest that sNAG-dependent defensin
expression requires Aktl in both endothelial cells and nocytes.
6.2.2.3. sNAG Treatment of Cutaneous Wounds Increase Defensin Expression
In Vivo
To confirm the dependence of Aktl for the expression of defensins in vivo, wild type
and Aktl null animals were used in an excisional wound healing model. Although most
mammalian ytes express a-defensins (human, rabbit, rat, and hamster), mouse leukocytes
do not express nsins. Therefore, B—defensin sion in these mouse models was
focused on. Treatment of ous wounds with a dried form of sNAG, a thin biodegradable
membrane, for three days results in a statistically significant increase in B-defensin 3 expression
in keratinocytes of wild type animals (Figure 9A). Involucrin (Watt, F.M., 1983, J Invest
Derrnatol. 81(1 Suppl): 5) staining (red) was used to mark the keratinocyte cell layers and
show that the expression of B-defensin 3 is confined to the mal layer. To assess if sNAG-
dependent defensin expression is dependent on Aktl, a similar assay was performed using an
Aktl null animal model. Wounds from Aktl null mice treated with sNAG membranes show a
markedly reduced induction of B—defensin 3 expression (Figure 9A). To better visualize the
epidermal layers that are expressing B-defensin 3, Figure 9B shows a representative image of a
sNAG treated wild type wound harvested on day 3. sNAG treatment of cutaneous wounds
induced B-defensin 3 expression mainly in the suprabasal layers of skin (Figure 9B).
Quantitative analyses shown in Figure 9C shows an approximate 5-fold increase in B-defensin 3
expression in sNAG treated wild type animals and that Aktl is required for this increase.
6.2.2.4. sNAG Treatment Increases the Kinetics of Wound Closure in WT
Animals
us results have shown an increased kinetics of wound e in diabetic mouse
models in response to sNAG treatment. sNAGs were tested for a similar affect in wild type
animals. Excisional wounds were created in wild type animals which were either treated with
the membrane form of sNAG or left untreated. Tissue sections were taken at l, 3 and 5 days
post wounding and subjected to H&E staining. As shown in Figure 10, sNAG treatment of wild
type wounds results in complete closure, as visualized by the solid line, at day 3 post wounding.
This occurs two days earlier than in the control wounds. Aktl null animals display a delay in
wound closure; these s do not fully close the wound until 7 days post wounding. The
delay in wound e in the Aktl null s is not rescued by sNAG treatment (data not
shown). These s suggest that sNAG not only induces in expression but also
increases wound healing cs in wild type mice and may be a novel and effective therapeutic.
6.2.2.5. sNAG is an Effective Antimicrobial Against S.Aureus
in peptides are known to possess antimicrobial properties that are active
against gram-positive and gram-negative bacteria. Since treatment of endothelial cells with
sNAG increases defensin expression (both a- and B-type) and treatment of cutaneous wounds
with sNAG dramatically increases [3- defensin 3 expression in vivo, the antimicrobial efficacy of
sNAG treatment in bacterially infected wounds was assessed.
To determine if sNAG decreases bacterial load in ous wounds, wild type and
Aktl null animals were subjected to cutaneous wound healing, ed by infection with
lococcus aureus. Infected wounds were either treated with sNAG or left untreated for 3
and 5 days post infection. As shown by the tissue gram staining in Figures 11A and 11B, wild
type animals treated with sNAG show a icant reduction in gram positive ng by day 5
post wounding as compared with untreated wounds. In contrast, gram stained tissue derived
from untreated wounds in Aktl null animals at 5 days post ng show an accumulation of
neutrophils which stain gram positive (Figure 11B), indicating a potential lack of ial
clearance in these s that is not rescued by sNAG treatment. These findings suggest that
Aktl null animals have a defect in immune clearance mechanisms which is not rescued by sNAG
treatment.
To quantitate sNAG-specific bacterial changes in colony forming units (CFU),
infected wounds from both wild type and Aktl null mice either sNAG treated or untreated were
harvested and cultured. As shown in Figure 11C, at 5 days post wounding bacterial number is
markedly reduced (10-fold) in wild type animals treatediwith sNAG. However, although the
number of bacteria detected in the Aktl null animals is reduced in comparison to wild type,
sNAG treatment had a little effect on absolute bacterial number in the Aktl null animals. At 3
days post-infection (Figure 11D), there is a similar 10-fold decrease in CFU in sNAG d
wild type mice as compared to untreated controls. The sNAG treated Aktl null animals show a
2-fold decrease in CFU as compared to untreated Aktl null animals. In general, the Aktl null
animals have a lower bacterial load per wound which may be reflective of an Aktl -dependent
effect on other processes in addition to defensin expression. These findings t that sNAG
treatment results in a marked reduction in bacterial load in ed cutaneous wounds in wild
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type mice but not in Aktl null mice, suggesting the possibility that defensins are mediating the
acterial se.
] To show that the antibacterial effect of sNAG treatment is not due to a direct effect of
the nanofibers on bacterial growth or on their survival,(S. aureus bacterial cultures were treated
in solution with ent amounts of sNAG, for 3 hours and colony forming units were
determined. As shown in Figure 11E, sNAG treatment had no direct effect on the growth of S.
, indicating that sNAG is not directly inhibiting bacterial growth and may then be working
via the up-regulation of defensins.
6.2.2.6. ation ofDefensin Peptide Mimics the sNA G Antibacterial Effect
To determine whether addition of defensin peptide can block bacterial infection
similarly to that shown for sNAG treatment, wild type mice were wounded and inoculated with.
S. aureus as described above and then treated with biologically active human B-defensin 3
peptide (l .Oum) for three days. Tissue biopsies were stained using a tissue gram stain and CFU
was quantitated. Figure 11 F-G shows the results of these experiments. Infected mice treated
with ensin 3 peptide have a decreased bacterial load, an approximate 7.5 fold decrease in
viable bacteria (Figure 11G), similar to that shown in wild type mice treated with sNAG.
One of the mechanisms by which defensin expression is induced is through
stimulation by bacterial LPS, possibly through the tion of Toll like receptors. ed,
M.E. and A]. Ouellette, 2005, Nat Immunol. 6(6):551-7.) To test whether bacterial infection
alone is able to induce B-defensin expression within the time periods tested, expression of B-
defensin was assessed in infected wounds from wild type animals after three days post
wounding. As shown in Figure 12A, bacterial infection alone does not induce the expression of
B-defensin within 3 days of infection, as is shown with sNAG treatment. However, in wild type
animals, sNAG treatment of infected wounds causes approximate 3- to 5-fold se in the
expression of B-defensin within a similar time period (Figure 12B). These findings suggest that
sNAG treatment rapidly induces the sion of defensin expression resulting in marked
bacterial nce in S. aureus infected wounds.
6.2.2.7. Antibodies Directed Against fl-Defensin 3 Block the Antibacterial
Effect ofsNAG
] Since defensins are secreted proteins, the inventors hypothesized that antibodies
directed against [3- defensin 3 may be able to block the antibacterial activities. To test this
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hypothesis, wounds were created, infected with S. aureus and treated with sNAG as described
above. The wounds were either treated with a B-defensin 3 dy or an isotype control; one
application each day for three days. Wound sections were obtained and stained for gram positive
bacteria. As shown in Figure 13A, sections derived from wounds treated with fi-defensin
antibody have more gram positive bacteria than those treated with isotype control antibodies. E
ach section shown was derived from the wound area directly under the scab. Quantitation of
CFU in these wounds shows that neutralization of B-defensin 3 prior to sNAG treatment in S.
aureus infected wounds results in a significh increase in bacteria. Animals that were treated
with an IgG isotype control show an approximate S-fold reduction in viable bacteria (Figure
13B). Taken together, these s suggest that sNAG treatment not only results in the increased
kinetics of wound g but also promotes an endogenous anti-bacterial se and supports
the use of this nanofiber as novel therapy to enhance wound healing while concurrently
decreasing wound infection.
6.2.3 Conclusions
The findings presented here trate that a marine diatom derived nanofiber,
sNAG, may be used as a novel and effective method to enhance wound healing while
concurrently decreasing wound infection. The data demonstrates that this FDA ed
material, which is presently used for hemostasis, stimulates the sion of both a-type and B-
'type defensins in y endothelial cells and an up-regulation of the B-type in primary
keratinocytes.
Defensins are an essential component of the innate immune system. These peptides
possess anti-microbial properties that are active againstigram-positive and negative bacteria,
fungi, and many viruses. ins are small (3-4 kDa), cysteine-rich cationic es found in
mammals, insects, and plants that are classified into different families (a, B, and 6) based on their
pattern of disulfide bonding. a-defensins are thought to be specific to neutrophils, are found in
very high concentrations (comprising approximately 5-7% of the total cellular n) (Ganz, T.
and RI. Lehrer, 1994, Curr Opin Immunol. 6(4):584-9), and are secreted during anti-microbial
responses (Ganz, T., 1987, Infect Immun. 568-7l). It has also been shown that rabbit
alveolar macrophages possess a-defensins in levels comparable to rabbit neutrophils. (Ganz, T.,
et al., 1989, J Immunol. 143(4):]358-65.) B-defensins are found in epithelial cell types such as
keratinocytes, mucosa] epithelial cells (Harder, J ., et al., 1997, Nature 387(6636):861; and
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Harder, J ., et a1., 2001, J Biol Chem. 276(8):5707-13) oral cavity tissues and salivary secretions
(Mathews, M., et a1., 1999, Infect Irnmun. 67(6):2740-5), and kidney where they can be up-
regulated in response to infectious or inflammatory stimuli (Ganz, T. and RI. , 1994, Curr
Opin Immunol. 6(4):584-9). Human nsin 1 (hDEFBl) is one of the most important
antimicrobial peptides in epithelial tissues. Defensin expression and secretion could be
extremely ant for creating wound therapeutics. The icrobial action by defensins is
considered part of innate immunity and is non-specific and broad spectrum. Therefore acquired
ial resistance, as seen with the overuse of antibiotics, is not an issue.
The data presented here also demonstrate that both in vitro and in viva Aktl is
required for in expression. sNAG treatment decreases Staph aureus infection of cutaneous
wounds in wild type control s but not in similarly treated Aktl null animals. It is also
important to note that sNAG stimulation of wild type cutaneous wounds results in an increased
kinetics of wound closure. Antibody blockade of nsin results in a reduction in the sNAG-
antibacterial activity. Taken together these findings suggest a central role for Aktl in the
regulation of defensin expression that is responsible for the clearance of bacterial infection and
that sNAG treatment activates these pathways in wild type animals.
The data that suggests that sNAG treatment of infected wounds could drastically
se bacterial load in ts, at least in part, by the induction of defensin expression.
Staphylococcus aureus is a bacterium frequently found colonizing the skin and in the nose. It is
still a common cause of nosocomial infections, ofien g postsurgical wound infections. S.
aureus infections in hospitals have plagued healthcare workers for years and the widespread
usage of antibiotics for treatment has lead to antibiotic resistant s. The data presented
herein shows that ent of Staph infected wounds with sNAG dramatically sed the
bacterial load. For example, the lack of dark purple gram staining in the treated WT mice in
Figures 11A and 113 indicates that the S. aureus infection has been cleared from these wounds.
Both the in vitro and in vivo data provides strong evidence for the use of sNAG (in ular,
Taliderm) in the treatment of wounds to decrease bacterial infection and therefore enhance
wound healing.
Control experiments indicate that the antibacterial effect of sNAG is not due to a
direct interaction of the material with the bacteria but is due to downstream affects such as the
regulation of defensins by Aktl activation. It is widely accepted that defensins are important
players in innate ty and function in antimicrobial activities. Most of the evidence for
their on is the direct killing of bacteria by in vitro mixing experiments with purified
defensin peptides (Selsted, ME. and AI. Ouellette, 2005, Nat Immunol. 6(6):551-7) or in
similar experiments as shown in Figure 11 with direct application of the purified active peptide.
The data here show that an induction of defensin expression in wild type animals using a topical
application of sNAG results in an cterial response. It has recently been shown that
transgenic mouse models sing the human defensin 5 gene are resistant to S. urium,
an infection that results in death of wild-type animals an, N.H., et al., 2003, Nature
422(6931):522-6) again suggesting the importance of defensins in the regulation of the
antimicrobial response.
It has been accepted that the a-subtype of defensins are specifically expressed in
neutrophils, whereas the B-type defensins are epithelial in origin. B-type defensin sion
induced in se to sNAG in human keratinocytes both in e and in the cutaneous wound
g model was detected. The in vivo data illustrates that B-defensin 3 is mainly expressed in
the suprabasal layers afier treatment with sNAG. This is consistent with previous data which
localized human B-defensin 2 to the spinous and granular layers of the skin. (Oren, A., et al.,
2003, Exp Mol Pathol. 74(2): 1 80-2.) The skin is in constant t with injury and infection
and functions not only as a mechanical barrier but also maintains the ability to mount an active
defense against infection. The expression of B- defensin in the outer layers of skin supports their
role in cutaneous innate immunity. However, the data show that sNAG specifically stimulates
the expression of three different (ii-defensins (l, 4 and 5) in endothelial cells. This is shown by
RT-PCR, gene array analysis, immunofluorescence and ELISA (data not shown). The
interaction between endothelial cells and leukocytes in tissue repair is one of the initial and most
important steps in wound healing. The process of extravasation of leukocytes from the
vasculature is initiated by chemotactic factors, therefore; it is interesting that a-defensins are
d by sNAG and may contribute to the ary neutrophil/endothelial cellular
interactions. More recently, it has come to light that defensins exhibit biological activities
beyond the inhibition of microbial cells, including their contribution to the adaptive immune
response by exhibiting chemotactic activity on tic (Hubert, P., et al., 2007, FASEB J.
21(1 1):2765-75) and T cells, monocytes, and hages (Garcia, J.R., et al., 2001, Cell Tissue
Res. 306(2):257-64) and keratinocytes (Niyonsaba, F., et al., 2007, J Invest Derrnatol.
127(3):594-604). Previous work shows that human beta defensins 1 and 2 have the ability to
chemoattract immature dendritic cells and T cells through the CC-chemokine receptor 6 (CCR6)
(Yang, D., et al., 1999, Science 286(5439):525-8), and that human beta defensin 2 can
chemoattract TNFa treated neutrophils via the CCR6 receptor (Niyonsaba, F H. Ogawa, and I.
Nagaoka, 2004, Immunology 1 1 1(3):273—81). Human nsin 2 and 3 have also been shown
to induce chemotaxis by interacting with CCR2, a receptor expressed on macrophages,
monocytes, and neutrophils. (Rohrl, J., et al., 2010, J l, 2010.) Interestingly, the data
show that sNAG treatment induces both a and B-defensin expression in endothelial cells. Taken
together, the recent data suggest that defensins may mediate wound healing not only by their
antimicrobial properties, but also by being chemotactic for other cell types necessary for proper
healing. However, ation of B-defensin 3 alone did not result in an increase in wound
closure (data not shown) implying that topical application of a single defensin does not sustain
the cellular interactions ed for sed chemo attraction, cellular tment and wound
closure.
The in vivo data using both wild type and Aktl ut animals confirms the
requirement for Aktl in sNAG-induced B-defensin 3 expression. Since mouse leukocytes do not
express a- defensins like most other mammalian leukocytes (Ganz, T., 2004, C R Biol.
327(6):539-49) in vivo (it-defensin staining of infiltrating immune cells was not possible.
Treatment of airway epithelial cells in vitro with alpha defensins 1-3 causes a dose and time-
dependent increased cell migration that requires activation of PI3K and MAPK pathways.
(Aarbiou, J., et al., 2004, Am J Respir Cell Mol Biol. 30(2):l93-201.) sNAG stimulation of
endothelial cells has been shown to result in the activation ofMAPK (Voumakis, J.N., et al.,
2008, J Vasc Res. 45(3):222-32) and in data presented here, pharmacological tion of MEK
also inhibits the expression of the defensins in vitro. These findings suggest that both pathways
impinge on the tion of in expression by sNAG, however, Aktl ablation results in a
marked reduction of its expression both in vitro and in vivo. In myeloid cells, B-defensin 1
expression is controlled at the level of transcription, in part, by the Ets-family member PU. 1.
(Yaneva, M., et al., 2006, J l. 176(11):6906-17; and Ma, Y., Q. Su, and P. Tempst, 1998,
J Biol Chem. 273(15):8727-40.) PU.1 is a downstream target of Aktl in the B-cell lineage.
(Rieske, P. and J.M. Pongubala, 2001, J Biol Chem. 276(11):8460-8.) In primary endothelial
cells it has been shown that Aktl is upstream of Etsl both in vitro and in vivo during Drosophila
tracheal development. (Lavenburg, K.R., et al., 2003, FASEB J. 17(15):2278-80.) sNAG
stimulation of endothelial cells results in increased expression of Etsl (probably through Aktl)
which is required for the migration of elial cells: (Voumakis, J.N., et al., 2008, J Vasc
Res. 45(3):222-32.)
Thus far, sNAG treatment has ed in a series of downstream activities;
hemostasis, cell migration, cell proliferation, increased wound closure, and as described here,
stimulation of the innate immune response resulting in acterial functions.
Given the dramatic increase of diabetic patients within the population who present
with chronic wounds and complications due to wound infection, new clinical ents are in
high demand. Here, marine derived pGlcNAc nanofibers are described that not only increase the
kinetics of wound healing but act to stimulate innate immunity thus providing anti-bacterial
activity. The obvious importance of these observations is the application to mial
infections. Of the nosocomial infections, surgical wound infections predominate; with statistics
g up to 8% of all surgical patients. The direct cost of these types of infections is
approximately 4.5 billion dollars per year. Given that defensins are part of the innate immune
, activation of these pathways will preclude the tion of resistant sms as well
as allow for the antibiotic-independent clearance of bacterial infection. Use of sNAG in a
hospital setting would defray much of the cost and markedly reduce the production of antibiotic
resistant s. Taken together, these findings suggest that these marine derived pGlcNAc
nanofibers will be highly beneficial in the clinical arena.
6.3 Example 3: sNAG Nanofibers Upregulate sion of a Number of Defensins and
Toll Receptor Genes.
This e demonstrates that a number of defensins and Toll-like receptors are up-
regulated by sNAG treatment of human endothelial cells.
Materials and Methods: Human Chip probes were printed on epoxy slides. HUVEC
cells were cultured as described in n 6.2, and treated with sNAG nanofibers (“sNAG”) for
hours. RNA was extracted with RNAsol (Teltest, Inc.) following cturer’s instructions,
amplified using Amino Allyl MessageAlVfPTM II aRNA amplification kit (Applied Biosystems),
and labeled. The slides were ed for hybridization with aRNA by soaking in blocking
solution (Sigma Tris-buffered saline pH8.0, in lOOOml dHZO, 1% BSAw/v, NaN; to 0.05%) at
RT O/N, then rinsed and dryed. Samples containing labeled target aRNA from sNAG-treated
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cells were hybridized with the slides (65u1/slide; red at 95°C for 5 min; hybridized for 48
hours at 37°C in 0.1% SDS and 5 X SSC and 1% BSA), rinsed and dryed. The slides were
scanned and hybridization detected using Perkin-Ehner Scan Array equipment and ScanArray
Express sofiware V3.0, updated. To identify up-regulated genes, microarray data was analyzed
using Agilent GeneSpring GX v.11 Bioinfonnation Data Analysis.
Genes of interest analyzed: IL-l, CEACAM3, SPAGl 1, defensins (“DEFA”=a-
defensin, and “DEFB”=B-defensin); Toll-like receptors (“TLR”), SIGIRR (Single 10 IL-l-
d receptor), and TRAF6 (TNF receptor associatedzfactor 6). Positive controls: 1433Z
(Tyrosinemonohydrogenase/tryptophan 5 monohydrogenase actition protein); GAPD
raldehydesphosphate ogenase); RPL13A (Ribosomal protein L13a); UBC
(Ubiquitin C); ACTB (Actin B).
Results: Results of the microarray gene chip analyses and Q-PCR validation of
microarray results are presented in Tables II-VI below. Using a custom gene chip it was
determined that a number of defensins and Toll-like receptors are up-regulated by sNAG
treatment of human elial cells.
Toll-like receptors (TLRs) are highly ved receptors that ize c
molecular ns of bacterial components leading to activation of innate immunity.
Interestingly, Drosophila lack an adaptive immune system but are still resistant to microbial
infections. (Imler, J.L. and IA. Hoffmann, 2000, Curr Opin Microbiol, 3(1): 16-22.) This host
defense is the result of an innate immune system that provides protection by synthesizing the
antimicrobial peptides dToll and 18-wheeler which are induced by TLRs. (Lemaitre, B., et al.,
1996, Cell 86(6):973-83; and Williams, M.J., et al., 1997, EMBO J. 16(20):6120-30.) Recent
work has also linked human defensin expression to TLR activation. Human fi-defensin 2 was
shown to be induced in airway epithelial cells in a TLR-2 dependent manner. , C.J., et al.,
2003, J Immunol. 171(12): p. 6820-6.) Toll-like receptor 4 has been shown to mediate human B-
defensin 2 inductions in response to Chlamydia pneumonia in monocytes. (Romano Carratelli,
C., et al., 2009, FEMS Immunol Med iol. 57(2):]16-24.) Importantly, the PI3K/Akt
pathway is a key component in TLR signal transduction, controlling cellular responses to
pathogens. (Weichhart, T. and MD. Saemann, 2008, Ann Rheum Dis. 67 Suppl 0-4.)
Since it is known that stimulation of TLR5 can lead to increased defensin synthesis, this work
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suggests the potential for sNAG as a stimulator of innate immunity and bacterial clearance via
the activation of Aktl.
Table 11: List of some genes up-regulated in response to sNAG stimulation
CEACAM3
SPAG11t-defensin-3 like molecule that exhibits antimicrobial ooroerties
TLRS
_—INDUCTION
LPS, viral roteins, Hseo Chlam dia
lL-1 rece-tor related TLR modulator m
Table III: Defensin Microarray Gene sion
(HUVEC Response to sNAG l 5 hours)
Gene Name [Oligo ID] HUVEC_105_48h37C normalized(Fold)
D107A_HUMAN [H300005354] 4.2 (2.6 to 5.2)
DEFB124 [H300001942] 3.8(1.6to 5.1)
DEFB126 [H200012496]
DEFB129 [H300005026] ‘ 5.2 (4.338 to 6.277)
ACTB_HUMAN [H300006234] 6.8 (6.603 to 7.284)
GAPD [H200007830] 16.9 (12.81 to 21.13)
RPL13A [opHsVO4TCOOOO41] 9.4 (7.311 to 12.01)
UBC [H200014214] 7.2 (5.789 to 9.979)
1433Z_HUMAN
[opHsVO4TC000038] 0.6 (0.4 to 0.844)
Table IV: DEFCB3 Microarray Gene tion
(AB Prism 7_0_00; sNAGjiflgg/ml), HUVEC for 5 hi
Fold difference
ACt= AACt= .
Sample DEFB3 1433z DEFB3 - ACttreated - 3.25553,
1433: ACt untreated
untreated
E I
f i
untreated ‘37.41iO.74 14.711026 1
} 22.71078 0.001078 3 1.4 (1.22-1.7)
E i
i i‘ f
treated i 1.0 17.841007 I 22.46110 3; 02411.0 ‘
1.8 (1.24—2.36)
Table V: Toll-Like Receptors Microarray Gene Expression
Gene Name [Oligo ID] Fold Change
SlGlRR [opHsv040000247;] 5-§9.5,(.3~915..t°,7.-925) . ,
[H300000701V]. (3-796 ten-33)
. 7-93
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. ... .
TLR8 [H200016915] V. 2.067 (1.8 to 2.2)
.._....._T.RAF5 [”220994951 ..
..4.--v-._2 -5557. (5.22.92 7.).
14332_HUMAN [opHsvo4Tc0000381 0.573 (0.4 to 0.844) I
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6.4 Example 4: sNAG and Long Fiber NAG Differ in Their Gene Expression Profiles.
This example demonstrates that sNAG nanofibers differ from long p-GlcNAc fibers
in their effect on gene expression, and specifically in their effect on expression of some of the
defensins and Toll-like receptors.
] Materials and Methods: Human Defensin Chip probes (concentration: 20uM,
quantity 18-20, solvent: SSC based spotting buffer) were printed on epoxy slides using standard
techniques. HUVEC and HaCat cells were cultured as described in section 6.2, and treated with
either long fibers (“LNAG”) or sNAG nanofibers (“sNAG”), for 2 hours or 20 hours. RNA was
extracted with RNAsol (Teltest, Inc.) following manufacturer’s instructions, and amplified using
Amino Allyl MessageAMPTM II aRNA cation kit ed Biosystems). During RNA
cation, aRNA from cells d with LNAG and aRNA from cells treated with sNAG
was differentially labeled with Cy3 or Cy5 fluorescent dyes. The slides were prepared for
hybridization with aRNA by soaking in blocking solution (Sigma Tris-buffered saline pH8.0, in
1000ml dHZO, 1%BSAw/v, NaN3 to 0.05%) at RT O/N, then rinsed and dryed. Samples
containing equal amounts of differentially labeled target aRNA from LNAG and sNAG-treated
cells were mixed, hybridized with the slides slide; denatured at 95°C for 5 min; hybridized
for 48 hours at 37°C in 0.1% SDS and 5 X SSC and 1% BSA), rinsed and dryed. The ing
exemplary graphs in Table VII illustrate experimental 'set up:
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The slides were scanned and hybridization detected using Perkin-Elmer Scan Array
equipment and ScanArray Express re V3.0, updated. For each slide, Cy5, Cy3 and
composite fluorescence was visualized. To identify up-regulated and down-regulated genes
microarray data was analyzed using Agilent n'ng GX v.1 1 Bioinforrnation Data Analysis.
Genes of interest analyzed: DEFAl, DEFA3, DEFA4, DEFA5, DEFA6, DEFBI, DEFBOl3A,
DEFB104A, DEFBIOSB, DEFB108B, DEFB112, DEFB114, DEFB118, DEFBl 19, DEFB123,
'DEFB124, DEFB125, DEFB126, DEFB127, DEFBIZS, DEFB129, DEFB131, and DEFB4
(“DEFA”=a-defensin, and “DEFB”=B-defensin); TLRl , TLRlO, TL2, TLR3, TLR4, TLRS,
TLR6, TLR7 and TLR8 =Toll receptor); SIGIRR (Single IG IL-l-related receptor);
IRAK2 (IL—1 receptor-associated kinase 1); TRAF6 (TNF receptor associated factor 6); D106A
(Ii-defensin 106), D107A (B-defensin 107). Negative controls: three random ces (1, 2, 3).
Positive controls: 1433Z inemonohydrogenase/tryptophan 5 monohydrogenase actition
protein); GAPD (glyceraldehydesphosphate dehydrogenase); RPL13A (Ribosomal protein
L13a); UBC (Ubiquitin C); ACTB (Actin B).
Results: Results of the microarray gene chip analyses are presented in Tables VIII
and IX below. Table VIII shows gene expression in human cal vein endothelial cells
(“HUVEC”) after 2h or 24 h re to either LNAG fibers or sNAG nanofibers. Table IX
shows gene expression in human keratinocyte cell line (HaCat) after 2h or 24 h re to
either LNAG fibers or sNAG nanofibers. The results demonstrate that gene expression profile
induced by long poly-N-acetylglucosamine fibers (“LNAG”) differs from the gene expression
profile induced by sNAG nanofibers (“sNAG”). Specifically, LNAG and sNAG differ in their
effect on expression of defensin genes and Toll receptor genes.
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Table VIII: Microarray Defensin Gene Expression in Human Umbilical Vein
elial Cells (HUVEC), Fold Change
[2h, [2h, [20h, [20h,
Name
LNAG] sNAG] LNAG] sNAG]
1433Z_HUMAN m 0.32 t0 14332 HUMAN -0 046 -0.180
ACTB_HUMAN -0 140 ACTB HUMAN o 874. 0413
D106A_HUMAN -1 376 -0.195 D106A_HUMAN 1.107 0.522
D107A_HUMAN 1.825 1.431 DlO7A_HUMAN -1.007 0.372
DEFA1 0 407. -1.107 DEFA1 -0 333 0.384
0.528 DEFA3 1 195 -2.335
-0.123 Efl-_ 2.535
DEFAS —0 863- 0.451 —0.476
DEFA6 1 969 0.805 4.402
_ m_
DEFBl 0 315 1.441 0413
DEF8103A 1 426 1.486 1.348
DEFB104A 1.296 2.260 DEF8104A 1.543 0.344
DEFBlOSB 0 616. 0.667 DEFBlOSB 0 723 -0.162
DEF8108B 2 210 0.441 DEF8108B 0 351 1.895
-0323 1.107
0.667 1.799
0631 0577
1.472 4530
1-814 —0-375
1.533 1357
1.969 4.053
0801 0.335
0000 1.035
528 2.233
005
608
-0.190
0.324
0984
0.208
~0.050
-0.631
0644
4.494
4.361
0.534
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EE@JMJDE— [1331; 1[—_ w 1
me um
—:.—_———
—:.————,m
———————
Table IX: Microarray Defensin Gene Expression in Human Keratinocyte
Cell Line (HaCat), Fold Change
- _
GA... —m-_C)APB
a -
—_— __—ACTB 0.130 0.447 _ ACTB 0.333 0.988
Negative 0.000 0.000 Negative 0.000 0 000
Negative 0 000 0.000 Negative 0 000 0.000
Negative 0.000 0.000 Negative 0.000 0.000
6.5 Example 5: Effect of Irradiation on sNAG nes
Method ofPreparation ofsNAG Membrane. The sNAG ne is derived from
microalgal pGlcNAc fibers produced as previously described (see is et al. US. Patent
Nos. 5,623,064; and 5,624,679, the content of each of which is incorporated herein by reference
in its entirety). Briefly, microalgae were cultured in unique bioreactor conditions using a defined
growth media. Following the harvest of microalgae from high-density cultures, fibers were
isolated via a stepwise separation and purification process resulting in batches of pure fibers
suspended in water for injections (wfi). Fibers were formulated into patches by concentration
and oven drying, and were ed and sterilized by irradiation. Fiber dimensions
average 20-50mm x l-2nm x ~ lOOum. Batches of fibers were individually quality controlled
using chemical and physical test parameters, and each batch met strict purity criteria prior to
release. Final batches were required to be substantially free of proteins, metal ions, and other
components. The fibers were then shortened by ation to produce sNAG membranes.
Briefly, the starting material contained 60 g of pGlcNAc slurry at a tration of 1 mg/mL.
The concentration of the pGlcNAc slurry was confirmed by filtering 5 mL into a 0.2 um filter.
L of pGlcNAc slurry ning 15 g pGlcNAc was filtered until formation of a wet cake.
The wake cake was then transferred into a foil pouch, which is a gamma radiation compatible
container, and subjected to 200 kGy gamma radiation. Other irradiation conditions were tested
for their effects on pGlcNAc compositions, as ed in Figure 14A.
Eflect diation on c Membranes. While irradiation reduces the
molecular weight of c, irradiation did not disturb the microstructure of the fibers.
pGlcNAc was irradiated under different conditions: as a dry, lyophilized material; as a dry
membrane; as a concentrated slurry (30:70 weight by volume); and as a dilute slurry (5 mg/ml).
A suitable molecular weight reduction (to a molecular weight of 500,000-1 ,000,000 daltons) was
achieved at an irradiation dose of 1,000 kgy for dry polymer, and 200 kgy for wet polymer
(Figure 14A).
The chemical and physical structure of the fibers was maintained throughout
irradiation as verified by infrared (IR) spectrum (Figure 14B), elemental assay, and scanning
electron microscopes (SEMs) analysis. Microscopic observation of ated fibers showed a
decrease in the particle length (Figures 14C and 14D). The majority of the fibers are less than
about 15 pm in length, with an average length of about 4 um.
6.6 Example 6: sNAG Nanofibers and Long Form Q-GlcNAc Fibers Differ in Their
Effects on Metabolic Rate and Serum Deprivation of Umbilical Cord Vein Endothelial Cells
] Materials and Methods. Pooled, multiple-donor human umbilical cord vein
endothelial cells (EC) (Cambrex) were maintained at 37°C with 5% C02 in endothelial basal
medium 2 (Cambrex) supplemented with EC growth medium 2 Quots as described by
Cambrex procedures. Serum starvation was performed at 80-90% ncy in RPMI-1640
supplemented with 0.1% fetal calf serum (Gibco BRL) for 24 h followed by stimulation with
VEGF 165 (20 ng/ml, R&D Systems) or with highly purified pGlcNAc nanofibers or sNAG
nanofibers in sterile water (provided by Marine Polymer Technologies, Inc., Danvers, Mass.,
USA) with the s indicated in the figure descriptions. For cellular proliferation/viability
assessment, 2 different assays were used: trypan blue exclusion by direct cell counts using a
hemacytometer and an MTT [3-(4,5-dimethylthiazol-2yl)-2,5—diphenyltetrazolium bromide]
assay in procedures described by the manufacturer (Promega).
s—pGlcNAc:
pGlcNAc did not aflect metabolic rate. As shown in Figure 15, pGlcNAc did not
result in a higher metabolic rate as ed by MTT assays, ting that this polymeric
material was not causing marked increases in cellular eration.
pGlcNAc ProtectedECfrom Cell Death Induced by Serum Starvation. To test if
pGlcNAc fibers had a direct effect on EC, serum-starved EC cells were treated with VEGF or
with different concentrations of pGlcNAc fibers. As shown in Figure 16 at 48 h and 72 h after
serum tion, as compared with the total number of cells plated (control), there was about 2-
fold reduction in the number of cells after 48 h or 72 h. At 48 h, this decrease in cell number was
rescued by the addition of VEGF or by the addition ofpGlcNAc fibers at either 50 or 100 ug/ml.
At 72 h, the decrease in cell number was rescued by the addition of VEGF or largely rescued by
the on of pGlcNAc fibers at 100 ug/ml. These results indicated that like VEGF, pGlcNAc
fiber treatment prevented cell death induced by serum deprivation.
Results—sNAG:
sNAG Induced Marked se in Metabolic Rate. As measured by MTT ,
sNAG at 50, 100 or 200 ug/ml resulted in a higher lic rate of EC than VEGF (Figure 17).
sNAG did not protect ECfiom cell death induced by serum deprivation. To test if
sNAG fibers had a direct effect on EC, serum-starved EC cells were treated with VEGF or with
different concentrations of sNAG fibers. As shown in Figure 18, at 48 h after serum starvation,
as compared with the total number of cells plated (control), there was about 2-fold reduction in
the number of cells. This decrease in cell number was rescued by the addition of VEGF but not
by the addition of sNAG fibers at 50, 100 or 200 ug/ml. These results indicated that not like
VEGF, sNAG fiber treatment did not prevent cell death induced by serum deprivation.
Conclusion: The above results trate ,that sNAG, unlike long form c,
increases the metabolic rate of serum-starved EC in a MTT assay and does not rescue apoptosis
of serum-starved EC in a trypan blue exclusion test.
6.7 Example 7. Preclinical Testing of sNAG
6.7.1 Test Article
A test article comprising sNAG produced as previously described in Section 6.2.1
Inc.
supra. was utilized. The test article was supplied sterile by Marine Polymer logies,
6.7.2 Biocompatibilig Testing - L929 MEM Elusion Test — ISO 10993-5
] Biocompatibility of the test article was tested in mouse fibroblast L929 mammalian
cells. No biological reactivity (Grade 0) was observed in the L929 cells at 48 hours, post
exposure to the test e. The observed cellular response obtained from the positive control
article (Grade 4) and negative control e (Grade 0) confirmed the suitability of the test
system. Based on the criteria of the protocol, the test article is considered non-toxic and meets
the requirements of the n Test, International Organization for Standardization (ISO)
10993-5 guidelines. See Table X below.
Table X:
Discrete mnsq‘roelasumules:m cell-13.235
Not more than 30% of the cells are round, loosely amazedE and Withotn
innatytopusmic grenades; l lyreecells are present
Not more than 50% of the caiis are round and iawié of immcytopfasmic
granular; no extensive cell lysis and empty areas between (elk
Not more than 70% of the (all layers contain rotated cells or are tysed
)I-euly cantata destruction of the cell layers
6.7.3 Intramuscular Implantation Test — ISO — 4 Week Implantation
6.7.3.1. als and Methods
To evaluate the potential of the test article to induce local toxic effects, the
uscular Implantation Test — ISO — 4 Week Implantation amuscular Implantation
Test”) was used. Briefly, the test article was implanted in the paravertebral muscle tissue of New
Zealand White rabbits for a period of 4 weeks. The test article was then evaluated separately
using two control articles: positive control Surgicel (Johnson and Johnson, NJ) and negative
l High Density Polyethylene (Negative Control Plastic).
Preparation of Test and Control Articles. The test article measured approximately 1
mm to in width and 10 mm in length. The two l articles were prepared. The positive
control, Surgicel (Cl), measured approximately 1 mm in width by 10 mm in length and was
received sterile. Negative l Plastic (C2), measured approximately 1 mm in width by 10
mm in length and was sterilized by dipping in 70% ethanol.
Pre-Dose Procedure. Each animal was weighed prior to implantation. On the day of
the test, the dorsal sides of the animals were clipped free of fur and loose hair was removed by
means of a vacuum. Each animal was appropriately anesthetized. Prior to implantation, the area
was swabbed with a surgical preparation solution.
Dose Administration. Four test article strips were surgically implanted into each of
the paravertebral muscles of each rabbit, imately 2.5 cm from the e and parallel to
the spinal column and approximately 2.5 cm from each other. The test article strips were
ted on one side of the spine. In a r fashion, positive control article strips (Surgicel)
were implanted in the contralateral muscle of each animal. Two negative control strips
(Negative l Plastic) were implanted caudal (toward the tail) to the test article and to C]
l implant sites on either side of the spine (total of four strips). A total of at least eight test
e strips and eight of each control article strips are required for evaluation.
Post-Dose Procedures. The animals were maintained for a period of 4 weeks. The
animals were observed daily for this period to ensure proper healing of the implant sites and for
clinical signs of toxicity. Observations included all clinical manifestations. At the end of the
observation period, the animals were weighed. Each animal was sacrificed by an injectable
barbiturate. Sufficient time was allowed to elapse for the tissue to be cut without ng.
Gross Observations. The paravertebral muscles in which the test or control articles
were implanted were excised in toto from each animal. The muscle tissue was removed by
carefully slicing around the implant sites with.a scalpel'and lifiing out the tissue. The excised
implant tissues were examined y, but without using excessive invasive ures that
might have disrupted the integrity of this tissue for histopathological evaluation. The tissues
were placed in properly labeled containers containing 10% neutral buffered formalin.
Histopathology. ing fixation in formalin, each of the implant sites was excised
from the larger mass of tissue. The implant site, containing the implanted material, was
examined macroscopically. Each site was examined for signs of inflammation, encapsulation,
hemorrhaging, necrosis, and discoloration using the ing scale:
0 = Normal
1 = Mild
2 = Moderate
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3 = Marked
After copic observation, the t material was lefi in-situ and a slice of tissue
containing the implant site was processed. Histologic slides of hematoxylin and eosin stained
sections were prepared by Toxikon. The slides were evaluated and graded by light microscopic
examination.
Pathological Assessment ofthe Eflects ofthe Implant The ing categories of
biological on were assessed by microscopic observation for each implant site:
1. atory Responses:
a. Polymorphonuclear leukocytes
b. Lymphocytes
c. Eosinophils
(1. Plasma cells
e. Macrophages
f. Giant cells
g. Necrosis
h. Degeneration
2. Healing Responses:
a. Fibrosis
b. Fatty Infiltrate
Each category of response was graded using the following scale:
0 = Normal
0.5 = Very Slight
1 = Mild
2 = Moderate
3 = Marked
The relative size of the involved area was scored by assessing the width of the area
from the implant/tissue interface to unaffected areas which have the characteristics of normal
tissue and normal vascularity. Relative size of the involved area was scored using the following
scale:
0 = 0 mm, No site
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0.5 = up to 0.5 mm, Very slight
1= 0.6 - 1.0 mm, Mild
2 = 1.1 - 2.0 mm, Moderate
3 = > 2.0 mm, Marked
The Intramuscular Implantation Test was ted based upon the following
references:
1. ISO 6, 1994, Biological Evaluation of Medical Devices — Part 6: Tests for Local
Effects Afier Implantation.
2. ISO 12, 2002, Biological Evaluation of Medical s — Part 12: Sample
Preparation and Reference Materials.
3. ASTM F981-04, 2004, Standard Practice for Assessment of ibility of
Biomaterials for Surgical Implants with Respect to Effect of Materials on Muscle and Bone.
4. ASTM F763-04, 2004, Standard Practice for Short Term Screening of Implant
Materials.
. ISO/IEC 17025, 2005, General Requirements for the Competence of g and
Calibration Laboratories.
The results of the Intramuscular Implantation Test were evaluated based upon the
following criteria:
1. Calculated Rating: For each implanted site, a total score is determined. The average
score of the test sites for each animal is compared to the average score of the control sites for that
animal. The average difference between test and control sites for all animals is calculated and
the initial Bioreactivity Rating is ed as follows:
0 - 1.5 No Reaction“
> 1.5 - 3.5 Mild Reaction
> 3.5 - 6.0 Moderate Reaction
> 6.0 Marked Reaction
* A negative calculation is reported as zero (0).
2. Modification of the Rating: The ogy observer reviews the calculated level of
bioreactivity. Based on the observation of all factors (e.g., relative size, pattern of response,
inflammatory vs. resolution), the pathology observer may revise the Bioreactivity Rating.
Justification for the modification to the rating is presented in the narrative report (A descriptive
narrative report regarding the biocompatibility of the test material is provided by the pathology
observer).
6.7.3.2. Results
The s indicated that the test article was non-reactive when implanted for 4
weeks (Bioreactivity Rating of 0.2) when compared to positive control Surgicel; and non-
ve (Bioreactivity Rating of 0.0) when compared to negative control High Density
Polyethylene (Negative Control Plastic).
Clinical observation. Table XI below shows results of the macroscopic evaluation of
the test article and control t sites indicated no significant signs of inflammation,
encapsulation, hemorrhage, necrosis, or discoloration at the 4 week time period. Some test sites
and the majority of the positive control, Surgicel, were not seen macroscopically and serial
sections were ted for microscopic evaluation.
Table XI:
Macroscopic Observations
4 “"901: Implantation
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‘Cl - Singing! {Due to the tuna: ofuw animal. wearable «new new attained for magic aim-sum)
C‘ - \eszmt Camel fixzh Demizy Peavfir‘tmc (Negative Cannot Ratio
gum Sc ale
0 - no on 2 - moderate reaction NSF - No Sir: Forms:
1 - mile warrior: 3 - malted manic: SKA - No: Appaxcabte
Implantation Site ations (Microscopic). Table XII below shows results of the
microscopic evaluation of the test article implant sites indicated no significant signs of
inflammation, fibrosis, hemorrhage, necrosis, or ration as compared to each of the control
article sites. The Bioreactivity Rating for the 4 week time period (average of three animals) was
0.2, (C1 — Surgicel) and 0.0 (C2 — ve Control Plastic) indicating no reaction as compared
to either ofthe control implant sites. The pathologist noted there was a moderate polymorphic
and histiocytic (macrophages) infiltrate around the in situ test article that was not unexpected
given the nature of the test material.
Table XII:
)fié'mscopic Obsen'atim}:
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C1 = Smgicel
C2 = Negative Central 3351‘ 0213513; y‘leae (Negndve Cosmo! Plastic)
Animal Tea Same (Ax-dag?) = 2.0
AnimalC! wmwmvw 1.5
Animal Cl Sour;(3.1%") = 1.4
AnimalScorc (Anna; Test Score ~_ Average (71 Scout) 3 0.5:
Animal Scone ge corr - Average CZ $0“) - 0.6"
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"" No sine found in ‘17:.
Table XII (Cont):
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Anibal Tea Scare (Ausnge‘)= LS
AninnJCI Stu: (Axmge')- 2:2
An‘hm‘lC: SmegAxué-m- 2.5
Animal 5mm (AsmgoTest Stow - Average Cl Score)- 11:1
Anibal Seer: (Army.- Teu Scow ~ Average C2 Smré) -= «0,7
' Ugdhmmothexfing-t Rating.
" N058: Will-r}. (3-2. 3:14 C34.
Table XII (Cont):
. Microscopic (Ibsen-gum: (tom;
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mnm-nmMinna-marr-
-mm-m-mm
urea-mmmmmmmmm‘
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Asian] Tess Seen: average") - 33
{man}.Cl Some(Axmgz') ‘ l .S‘
Astana} (:2 Scale. ") - 2.5%
Animal Scone [AvHugeTm Stow - Average Cl Scone) - 05
Animal Score (Axum Test Score Av.craze C2 Scone) - 4).]
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Animal Scare. 60968 - 0.5 ~11]
Biorc'x‘d‘iry Rating - 0.: - No Reaction
Kinemu'vlty Rating -' 90-1 - No Reaction
6.7.4 Intracutaneous Iniection Test - ISO 10993-10
USP 0.9% Sodium Chloride for Injection (NaCl) and Cottonseed Oil (CSO) extracts
of the test article were ted for their potential to e irritation after intracutaneous
injection in New Zealand White rabbits. The test article sites did not show a significantly r
biological reaction than the sites injected with the control article. Based on the ia of the
protocol, the test article is considered a negligible irritant and meets the requirements of the ISO
guidelines. Results are shown below in Table XIII.
WO 42581
Table XIII:
Intracutaneous Test Skin Reaction Scores
NaCI Extract
Site Numbers
T—l r-s c-1 02 ca c-4 05
0/0 0/0 0/0 0m cm 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 cm 0/0 010 0/0 0/0
619” Nam
o/o o/o oxo 0/0 0/0 0/0 0m 0m 0/0 0/0
0/0 0/0 0/0 0/0 0/0 om 0/0 0/0 010 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
= Immediately afier injection, not used for the evaluation criteria‘
Overall Mean Score' for Test Article = 0.0
Overall Mean Score' for Control Article = 0.0
ence between Test Article and Control Article Overall Mean Score = 0.0—0.0‘= 0.0
CSO Extract
Animal # Vehicle Time Scorin ER/ED
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
48 hours 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
72 hours 010 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0
= Immediately afler injection, not used for the evaluation criteria.
Overall Mean Score' for Test Article = 0.0
Overall Mean Score' for Control Article = 0.0
Difference between Test e and Control Anicle Overall Mean Score = 0.0—0.0 = 0.0
ER = Erythema; ED=Edema; T = Test Sites; C = Control Sites
Overall Mean Score = Total erythema plus edema scores divided by 12
(2 s x 3 scoring periods x 2 g ries)
6.7.5 Kli man Maximization Test — ISO 10993-10
UPS 0.9% Sodium Chloride for Injection (NaCl) and Cottonseed Oil (CSO) extracts
of the test article elicited no intradermal reaction in Hartley guinea pigs at the challenge (0%
sensitization), following an induction phase. Therefore, as defined by the scoring system of
Kligrnan, this is a Grade 1 reaction and the test article is classified as having weak allergenic
potential. Based on the criteria of the protocol, a Grade I sensitization rate is not considered
2012/033782
significant and the test article meets the requirements of the ISO 10993-10 guidelines. Results
are shown below in Table XIV.
Table XIV:
Skin Examination Data
Scores Percent
Allergenic
Animals
Potential
be 25 Do 26 Sensitized
SwquMAuN— Male 0
Male 0
Male 0
Male 0
Test Article Male 0
(NaCl Extract) Female 0
Female 0
Female 0
Female 0
Female 0
Test Article 0
(CSO Extract) 0
Negative 0
Control (NaCl)
Negative 0
Control (CSO)
Positive Control
3 WNNN—OOOOOOOOOOOOOOOOOOOOOOOOOOOOOO N-I—I-‘OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Extreme
(DNCB) 3
0-8 I Weak
ll Mild
Moderate
Strong
Extreme
The test results are interpreted based upon the percentage sensitization observed.
6.8 Example 8: sNAG Nanofibers Are ive to Treat Viral ions in Human
This example demonstrates that sNAG nanofibers have a potent anti-viral , in
particular, against Herpes Simplex Virus, in vivo. Specifically, this example shows that sNAG
nanofibers are effective to treat cold sores associated with HSV infection when administered
topically, at the site of herpes infection, to human patients. In particular, this example
demonstrates that topical treatment of human patients with compositions comprising sNAG
nanofibers reduces painfulness and duration of cold sore symptoms associated with HSV
infection.
Hemes Simplex Virus Infection
Herpes simplex labialis is a common infection that is estimated to affect 20% to 40%
of the population (Spruance, 1992; Lowhagen, 2002). The majority of these infections are due to
herpes simplex type I, with a smaller number being attributed to herpes x type II.
Most individuals suffer primary infection with herpes gingivostomatitis early in life.
Following primary infection, the virus ishes itself in the inal sensory ganglia as a
chronic latent infection. Reactivation of the virus is common and typically presents as herpes
labialis along the llion border of the lip. Primary ion with herpes simplex is marked
by a long period of viral multiplication and shedding (Harmenberg, 2010). After viral replication
is terminated, the lesions heal rapidly. Recurrent herpes labialis is generally cleared more
rapidly than y infection due to acquired immune response. Unfortunately, the vigorous
immune response results in icant inflammation leading to al symptoms including
pain, redness and ng.
Recurrent herpes is marked by distinct stages (Harmenberg, 2010). The stages occur
in a table sequence as follows: prodrome, redness, papule, e, ulcer, hard crust, dry
flaking residual swelling, and normal healed skin. The disease is most severe during the
vesicular, ulcer and crust stages that are also ed to as the ulcerative or classical lesions.
Currently existing therapies for herpes labialis have focused principally on decreasing
viral replication with either oral or l antiviral medications. Unfortunately, since the viral
replication phase is quite brief in recurrent infections these medications have only modest
success, decreasing healing time of herpetic lesions by approximately 10% (Harmenberg, 2010).
Study Objectives
Primary Endpoints. The primary objectiveof this study was to explore the efficacy of
sNAG ers1n the treatment of herpes labialis peri--oral lesions, and to explore the duration
and intensity of pain of herpes labialis peri-oral lesionsin subjects treated with sNAG
nanofibers.
Inclusion Criteria
Subjects who met all of the following inclusion criteria were le for ment
into the study:
1. Be a generally healthy man or woman 18 years of age or older;
2. Have recurrent herpes labialis as defined by a history of three (3) or more cold
sore recurrences on the lips and/or skin surrounding the lips in the us 12 months;
3. During .>_ 50% of recurrent episodes, develop a classic herpetic lesion (i.e.,
e, ulcer, or hard crust);
] 4. Have the majority of their cold sore recurrences proceeded by a well defined
history of mal symptoms including redness, pain, burning, tingling,
swelling or a tight sensation of the lip at the site of the outbreak;
5. Primary cold sore recurrence for the study must be located on or within 1 cm of
the lip without mucosa] involvement.
Study Materials
sNAG nanofibers were supplied in five white plastic tubes containing 200 microliters
each (with sNAG concentration of 50 r‘ng/mL).
Administratioii
10 subjects (human patients) participated in the study. The sNAG ers (the
majority of the sNAG nanofibers used were between about 1 to 15 microns in length) were
applied to the cold sore once a night for five (5) consecutive nights, immediately prior to
bedtime.
Study Assessments and Diary
Subjects participating in the study had their herpetic ulcer evaluated by the study
team based upon a Cold Sore Clinical Rating scale as shown in Table XV.
Table XV: Cold Sore Clinical Rating
m:- Descri-tion
Skin appears normal. Subject reports pain, burning,
itchin, tin lin, swellin_, or a tiht sensation of the li .
E hema/Macule Redness an oarent. No n or skin ion.
Papule/Edema
sm- Descri-tion
Any presence of a blister-like elevation with fluid
visible throuh the stratum comeum.
Ulcer/Soft Crust r collapsed forming an ulcer or soft crust. Ulcer I
4 floor may be moist or n spongy or moist crusty
material.
Hard Crust Ulcer dried to form a noticeable hard consolidated mass
or scab or the fist scab has come off and a second or
third smaller scab has formed.
E y lesion complex has resolved. Hard crust
sloughed, wound essentially re-epithelialized. Residual
swellin_, redness o flakin; ma be resent
Aborted Primary lesion complex did not develop beyond Stage 2
(Papule/Edema). Skin appears normal and symptoms
have ed.
ts were provided instructions to record the date and time of the cold sore
recurrence and time of each treatment application and severity of pain. Pain was assessed using
a 10 point l scale (0 to 10) where 0 = no pain and 10= severe pain. Figure 19 shows
Numeric Pain Intensity Scale utilized in the study. Table XVI shows the Investigator End-of-
Study Global Assessment of Therapy, including the question posed to the Investigator and the
scale by which the effectiveness of therapy was measured. Table XVII shows the Subject End-
of-Study Global Assessment of Therapy, including the question posed to the subject and the
scale by which the iveness of therapy was measured. Table XVII also shows that the
subjects were asked “Was this cold score recurrence resolved faster than prior events?” and the
subjects could reply “Yes” or “No” to this question.
Table XVI: Investigator End-of-Study Global Assessment of Therapy
Based on the clinical course of this cold sore recurrence, what is your assessment of
effectiveness of thera ?
(10)
Excellent
(1) (2) (3) (4) (5) (6) (7) (8) (9) ReSponse
Response
. t0
to Therapy
Thera.
Table XVII: Subject End-of-Study Global ment of Therapy
reeunrenee “to vowmthera .
(10)
Excellent
Response Response
to to
Thera .
Results and Discussion
Ten patients were enrolled and completed the study bed above. The research
team confirmed that the cold sores in these patients conformed to the clinical rating and followed
the patients throughout the prescribed therapy.
Investigator —Study Global Assessment of Therapy of the 10 subjects enrolled
in this study is presented in Table XVIII. At the end of the study, Investigator was asked the
following question: based on the clinical course of this cold sore recurrence, what is your
assessment of effectiveness of therapy? Investigator’s responses are presented in Table XVIII.
Table XVHI:
Investigator
lAssessment
Patient 1 \l
Patient 2
Patient 3
Patient 4
t 5 10
Patient 6
Patient 7
Patient 8
Patient 10
Avera _e .—
Std 0.94
ingly, the Investigators found that topical treatment of cold sores known to be
caused by a Herpes Simplex virus with sNAG nanofibers was a highly effective y.
Assessment of the effectiveness of therapy by the 10 subjects enrolled in this study is
presented in Table XIX. The patients undertook the topical sNAG nanofiber stration (as
described above) and documented ent application and severity of pain. Patients responded
the questions and reported the results. Subjects were asked the following questions: Based on
this cold sore recurrence, what is your assessment of effectiveness of therapy? Was this cold
sore recurrence resolved faster than prior events? Subjects’ responses are presented in Table
XIX.
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The results of the study demonstrate that application of sNAG nanofibers reduced the
duration and pain associated with recurrent herpes labialis. Both investigators and patients
reported that the therapy was highly effective in treating the condition.
The results from this study apply not only to herpes is but indicate the ial
of ng ulcerations caused by viruses including but not limited to genital herpes and herpes
zoster.
] Next, effectiveness of topical application of sNAG nanofibers is to be evaluated in a
placebo-controlled study, using sNAG nanofibers at a concentration of 25 mg/ml.
References
Spruance SL. The natural history of recurrent oral-facial herpes simplex virus
ion. Semin Dermatol 1992; 11: 200—206.
Lowhagen GB, Bonde E, Eriksson B, Nordin P, Tunback P, Krantz I. Self-reported
herpes is in a Swedish population. Scand J Infect'Dis 2002; 34: 664—667.
Harrnenberg J, Oberg B, Spruance S. Prevention of ulcerative lesions by episodic
treatment of recurrent herpes labialis: A ture review. Acta Derm Venereol. 2010 Mar;
90(2): 122-30.
Hull C, McKeough M, Sebastian K, Kriesel J, Spruance S. Valacyclovir and topical
clobetasol gel for the episodic treatment of herpes labialis: a patient-initiated, double-blind,
placebo-controlled pilot trial. J Eur Acad Dermatol Venereol. 2009 Mar; 23(3):263-7.
6.9 e 9: sNAG Nanofibers Are Effective to Treat Inflammatog Bowel Disease
in Vivo.
This example shows that sNAG nanoflbers are effective to treat and/or prevent the
pment of inflammatory bowel disease. In particular, this example shows that rectal
administration of sNAG nanofibers is effective to treat and/or prevent ation associated
with chemically-induced inflammatory bowel disease in an animal model of the disease.
Inflammatog Bowel Disease
One of the common chronic inflammatory diseases with significant impact in
ity and quality of life is inflammatory bowel e (IBD) including Crohn’s disease and
tive colitis (UC). There are two main questions associated with the pathophysiology of
this disease, i.e. what is the primary trigger and how the disease progresses s chronic
inflammation, ineffective repair of the injured tissue and compromised healing. Increasing
interest in the second question lately is associated with the impact new findings can have in the
effective treatment of the disease and the improvement the quality of life.
Materials and Methods:
] The model used in this study is the duced ulcerative colitis that consists of
administration of 3% D88 (dextran sodium sulphate) via drinking water for 7 days to a mouse.
The peak of the inflammatory on is ed on day 7 and is followed by a period of repair
of the injured colonic tissue and ultimately regeneration or progression to c disease and
development of fibrosis.
The Chart showing mental set up is presented in Figure 20. At Days 0 through
7 D88 was administered via drinking water to all of the animals (mice) used in the study. One
group of animals (N=10) was administered 100 pl of sNAG nanofibers (at a concentration of 12
mg/ml; the majority of sNAG ers used were between about 1 to 15 s in length),
rectally, at Day 0 and Day 3 of the study (test group). Second group of animals (N=10) was
administered saline control, rectally, at Day 0 and Day 3 of the study (control group). All mice
were sacrificed at day 7, and their atory response was evaluated by histological analysis
of intestinal epithelium. Histological analysis was performed via staining of the sections of
intestinal epithelium, such as H&E staining.
Protocol for H&E staining of intestinal epithelium ns. For deparafinization,
ns were initially incubated in xylene for 30 min followed by decreasing concentrations of
ethanol (100%x2 for 3min, 95% for 3min, 75% for 3min, 50% for 3min). The sections remained
in running water for 5 min to remove excess ethanol. Then, ns were immersed in
hematoxylin for 20 sec and washed with 1-2 immersions in clean water. Sections were
subsequently incubated in eosin for 45 sec and washed again in clean water. Then, sections were
incubated in increasing concentrations of ethanol (80% for 3086C, 90% for 305cc and 100% for 2
min), followed by incubation in xylene for 9 min. Subsequently, sections were mounted with
DPX mounting medium and placed under a coverslip.
Results and Discussion
Figures 21 and 22 show that in the DSS-induced mouse model of inflammatory bowel
disease, treatment with sNAG nanofibers resulted in: significant reduction in the inflammatory
reaction (as judged by published histological criteria) compared to the control mice; and
protective s in the subacute phase of DSS-colitis, acting in t with repair mechanisms
to t tissue remodeling including the intestinal epithelium.
Specifically, Figure 21 shows improved histological findings related to the
inflammatory process in the mice administered sNAG nanofibers but not in control mice. In
ular, reated goup mice but not control mice displayed decreased edema (seeFigures
21A and 21B; the area of edema is indicated by a thin arrow and a bracket), and reduced
leukocytic infiltration (see Figures 21A and 218; the leukocytic infiltration is indicated by a
thick arrow).
Figure 22 shows staining for fibrosis in sections from mice treated with sNAG
nanofibers and from control mice. The ences in the inflammatory response between
sNAG-treated mice and control mice are evident. In particular, the control group shows signs of
increased fibrosis (see Fig. 22A), whereas sNAG-treated group does not (see Fig. 22B).
The presented data show that sNAG ers are effective to treat and/or prevent
ation associated with inflammatory bowel e in an animal model of the disease.
These findings demonstrate the potential therapeutic application of sNAG nanofibers in the
treatment of IBD patients. In addition, advantageously, sNAG nanofibers can be applied locally
by topical application (such as rectally via a suppository), and thus avoid systemic side-effects
(common to systemically-administered drugs).
7. ORATION BY REFERENCE
The disclosures of all references such as publications, patents and patent applications
cited in this specification are hereby incorporated by reference herein in their entireties as if each
individual publication or patent application were specifically and individually indicated to be
incorporated by reference. Although the foregoing invention has been described in some detail
by way of ration and example for purposes of clarity of understanding, it will be readily
nt to those of ordinary skill in the art in light of the teachings of this invention that certain
changes and modifications may be made thereto without departing from the spirit or scope of the
appended claims.
Claims (45)
1. Use of a composition sing shortened fibers of poly-β- 1→4-N-acetylglucosamine (“sNAG nanofibers”) in the manufacture of a medicament for treating a viral infection or a viral disease in a human subject having a viral infection or a viral disease, wherein the treating ses topically administering the composition comprising the sNAG nanofibers to the human subject, and wherein (i) more than 50% of the sNAG bers are between about 1 to 15 µm in length, or (ii) the average length of the sNAG nanofibers is less than 15 µm.
2. The use of claim 1, which is for treating a viral infection.
3. The use of claim 2, wherein the ng comprises administering the sNAG nanofibers in an amount effective to: (i) reduce the severity of the viral infection or one or more symptoms of the viral infection, (ii) reduce the duration of the viral infection or one or more symptoms of the viral ion; (iii) reduce the viral load or count; and/or (iv) eradicate one or more symptoms associated with the viral infection.
4. The use of claim 1, which is for treating a viral disease.
5. The use of claim 4, wherein the treating comprises administering the sNAG nanofibers in an amount effective to: (i) reduce the severity of the disease or one or more symptoms of the disease, (ii) reduce the duration of the disease or one or more symptoms of the disease, (iii) t the progression of the e or one or more ms of the disease, and/or (iv) reduce the number of symptoms associated with the disease.
6. Use of a ition comprising shortened fibers of poly-β- 1→4-N-acetylglucosamine (“sNAG nanofibers”) in the manufacture of a medicament for preventing a viral disease in a human subject at risk of developing a viral disease, wherein the treating comprises topically administering the composition comprising sNAG nanofibers to the human subject, and wherein (i) more than 50% of the sNAG nanofibers are between about 1 to 15 µm in length, or (ii) the e length of the sNAG nanofibers is less than 15 µm.
7. The use of claim 6, wherein the treating comprises administering the sNAG nanofibers in an amount effective to prevent the onset, development or recurrence of a viral disease, and/or one or more symptoms thereof.
8. The use of any one of claims 1-7, wherein the viral infection or the viral disease is a topical viral infection or a topical viral disease.
9. The use of any one of claims 1-8, wherein the treating comprises administering the composition comprising the sNAG bers to the skin or mucous membrane of the subject.
10. The use of any one of claims 1-9, wherein the treating comprises administering the composition comprising sNAG nanofibers topically at the site of, or in the proximity to the site of, a symptom of the viral infection or the viral disease.
11. The use of claim 10, wherein the symptom of the viral infection or the viral disease is a rush, a lesion, a cold sore, a blister, a papule, a vesicle or a crust.
12. The use of any one of claims 1-3 and 8-10, n the viral ion is an HSV infection.
13. The use of claim 12, wherein the treating comprises stration lly at the site of, or in the proximity to the site of, a cold sore or a lesion associated with the HSV ion.
14. The use of claim 12 or 13, wherein the HSV infection is a recurrent herpes simplex labialis.
15. The use of any one of claims 1-14, wherein the sNAG nanofibers are formulated as a ne, a powder, a suspension, a liquid solution, an ointment, a cream, a spray, or a gel.
16. The use of any one of claims 1-15, wherein more than 50% of the sNAG nanofibers are between about 1 to 15 µm in length.
17. The use of any one of claims 1-15, wherein the average length of the sNAG nanofibers is less than 15 µm.
18. The use of any one of claims 1-17, wherein more than 50% or at least 95% of the sNAG nanofibers are no greater than 10 µm in length.
19. The use of any one of claims 1-17, wherein the average length of the sNAG nanofibers is from about 4 to 7 µm.
20. The use of any one of claims 1-17, wherein more than 50% of the sNAG nanofibers are between about 1 to 12 µm in length, or between about 1 to 8 µm in length.
21. The use of any one of claims 1-20, wherein the sNAG nanofibers were produced by irradiation of poly-N-acetylglucosamine with a dose of irradiation that reduces the average length of the sNAG nanofibers to less than about 15 µm in length.
22. The use of any one of claims 1-21, wherein the sNAG nanofibers were ed by irradiation of poly-N-acetylglucosamine and/or a derivative thereof, and wherein (i) the poly- etylglucosamine and/or a derivative thereof was ated in the form of dry fibers, a dry fiber membrane or a dry lyophilized material at the dose of irradiation of 500-2,000 kgy, or (ii) the poly-N-acetylglucosamine and/or a derivative thereof was irradiated in the form of a suspension, a slurry or a wet cake at the dose of irradiation of 100-500 kgy.
23. The use of any one of claims 1-21, wherein the sNAG nanofibers were produced by irradiation of poly-N-acetylglucosamine, and wherein (i) the poly-β-N-acetylglucosamine was irradiated in the form of dry fibers, a dry fiber membrane or a dry lyophilized al at the dose of irradiation of 500-2,000 kgy, or (ii) the poly-N-acetylglucosamine was irradiated in the form of a suspension, a slurry or a wet cake at the dose of ation of 100-500 kgy.
24. The use of any one of claims 1-21, wherein the sNAG nanofibers were ed by irradiation of poly-N-acetylglucosamine and/or a derivative thereof, and wherein (i) the poly- β-N-acetylglucosamine and/or a derivative thereof was irradiated in the form of dry fibers, a dry fiber membrane or a dry lyophilized material at the dose of irradiation of 750-1,250 kgy, or (ii) the poly-N-acetylglucosamine and/or a tive f was irradiated in the form of a suspension, a slurry or a wet cake at the dose of irradiation of 150-250 kgy.
25. The use of any one of claims 1-21, wherein the sNAG nanofibers were produced by irradiation of poly-N-acetylglucosamine, and wherein (i) the poly-β-N-acetylglucosamine was irradiated in the form of dry fibers, a dry fiber membrane or a dry lyophilized material at the dose of irradiation of 750-1,250 kgy, or (ii) the poly-N-acetylglucosamine was irradiated in the form of a suspension, a slurry or a wet cake at the dose of irradiation of 150-250 kgy.
26. The use of any one of claims 21-25, wherein the irradiation is gamma irradiation.
27. The use of any one of claims 1-26, wherein the sNAG nanofibers were produced from a microalgal poly-N-acetylglucosamine.
28. The use of any one of claims 1-27, wherein the sNAG nanofibers comprise N- acetylglucosamine monosaccharides and/or glucosamine ccharides, and wherein more than 70% of the monosaccharides of the sNAG nanofibers are N-acetylglucosamine monosaccharides.
29. The use of any one of claims 1-28, wherein the sNAG nanofibers comprise N- acetylglucosamine monosaccharides and/or glucosamine ccharides, and wherein more than 90% of the monosaccharides of the sNAG bers are N-acetylglucosamine monosaccharides.
30. The use of any one of claims 1-29, wherein the sNAG nanofibers comprise N- acetylglucosamine monosaccharides and/or glucosamine monosaccharides, and wherein more than 95% of the monosaccharides of the sNAG nanofibers are N-acetylglucosamine monosaccharides.
31. The use of any one of claims 1-30, wherein the sNAG bers are non-reactive when tested in an elution test, an intramuscular implantation test, an utaneous test, and/or a systemic test.
32. The use of claim 31, wherein the sNAG nanofibers are non-reactive when tested in an intramuscular implantation test.
33. The use of any one of claims 1-32, wherein the sNAG nanofibers increase the metabolic rate of serum-starved human cal cord vein endothelial cells in a MTT assay and/or do not rescue apoptosis of serum-starved human umbilical cord endothelial cells in a trypan blue exclusion test.
34. The use of any one of claims 1-33, wherein the medicament does not comprise an additional anti-viral agent.
35. The use of any one of claims 1-34, wherein the ng does not include administration with an additional anti-viral agent.
36. The use of any one of claims 1-35, wherein the medicament does not comprise an additional anti-inflammatory agent.
37. The use of any one of claims 1-36, wherein the medicament does not comprise an additional agent that boosts the immune system.
38. The use of any one of claims 1-37, wherein the medicament does not comprise an additional active ingredient.
39. The use of any one of claims 1-38, wherein the treating does not comprise administration of the composition in ction with another therapy.
40. The use of any one of claims 1-39, wherein the infrared spectrum (“IR”) of the sNAG bers is about the same as or equivalent to that of non-irradiated lgal poly-N- glucosamine or a derivative thereof.
41. The use of any one of claims 1-40, wherein the sNAG nanofibers have the microstructure of the fibers.
42. The use of any one of claims 1-41, wherein the sNAG nanofibers have the chemical and physical structure of the fibers as determined by infrared (IR) spectrum, elemental assay and scanning electron microscopic (SEM) analyses.
43. The use of any one of claims 1-42, wherein the composition comprises shortened fibers of -1→4-N-acetylglucosamine.
44. The use of claim 1, substantially as herein described or exemplified.
45. The use of claim 6, ntially as herein described or exemplified. A. NAG sNAG 3.... 0'5 1 EM SCR shAkt1 0L531 nectin R) lL-1, VEGF, Defensins Other Target Genes
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ715595A NZ715595A (en) | 2011-04-15 | 2012-04-16 | Treatment of disease with poly-n-acetyglucosamine nanofibers |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201161476237P | 2011-04-15 | 2011-04-15 | |
US61/476,237 | 2011-04-15 | ||
PCT/US2012/033782 WO2012142581A1 (en) | 2011-04-15 | 2012-04-16 | Treatment of disease with poly-n-acety glucosamine nanofibers |
Publications (2)
Publication Number | Publication Date |
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NZ616500A NZ616500A (en) | 2016-03-31 |
NZ616500B2 true NZ616500B2 (en) | 2016-07-01 |
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