WO2021195438A1

WO2021195438A1 - Treatment of respiratory damage

Info

Publication number: WO2021195438A1
Application number: PCT/US2021/024243
Authority: WO
Inventors: Bradley Robinson
Original assignee: Predictive Technology Group, Inc.
Priority date: 2020-03-25
Filing date: 2021-03-25
Publication date: 2021-09-30

Abstract

Disclosed herein are methods for treating a symptom in a human at least in part produced from or occurring from a viral infection comprising: administering a therapeutically effective amount of allogenic stem cells, to a human to treat the symptom.

Description

TREATMENT OF RESPIRATORY DAMAGE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent document claims priority to and benefit of U.S. Provisional Patent Application No. 62/994,649, entitled “Treatment of Respiratory Damage from a Coronavirus Infection” filed on March 25, 2020. The entire content of the aforementioned patent application is incorporated by reference as part of the disclosure of this patent document.

BACKGROUND

[0002] Viral infection can lead to severe complications, such as lung damage, in subjects if left untreated or if treatment is ineffective. However, development of traditional antiviral regimens can be labor-intensive and costly and may not be beneficial in all cases. For example, mutation of viruses can hinder development of effective antiviral therapies and/or reduce the efficacy of a treatment over time in a population. New approaches for the treatment of viral infections are needed.

SUMMARY

[0003] The present disclosure generally relates to methods and compositions useful in treating a viral infection in a subject. In various aspects, a method for treating one or more symptoms in a subject comprises: administering a therapeutically effective amount of allogenic stem cells to the subject to treat the one or more symptoms, wherein (i) the one or more symptoms comprise respiratory damage, (ii) the allogenic stem cells are from at least in part Wharton’s jelly, and (iii) the allogenic stem cells are administered in a formulation in unit dose form. In some cases, the one or more symptoms are at least in part produced from or occurring as a result of a viral infection. In some cases, the one or more symptoms are at least in part produced from or occurring as a result of a non-viral cause. In some cases, the subject has emphysema. In some cases, the allogenic stem cells comprise mesenchymal stem cells (MSCs). In some cases, the MSCs are not expanded in vitro. In some cases, the MSCs express CD73, CD90, CD105, or any combination thereof. In some cases, the MSCs do not substantially express CD14, CD34, CD45, HLA-DR, CD 19, or any combination thereof. In some cases, the allogenic stem cells are harvested mechanically. In some cases, the administering is performed during onset of a viral infection. In some cases, the administering is performed after onset of a viral infection. In some cases, the administering is performed before and after onset of a viral infection. In some cases, the method further comprises administering to the subject remdesivir, chloroquine, lopinavir, ritonavir, favilavir, corticosteroid, interferon-beta, antivirals, vitamin C, a salt thereof, or any combination thereof. In some cases, the method further comprises administering to the subject oxygen, saline, or any combination thereof. In some cases, the method further comprises administering to the subject azithromycin, amoxicillin, cephalosporin, fluroquinolone, ampicillin, sulbactam, doxycycline, an antibiotic, a salt of any of these, or any combination thereof. In some cases, further comprises administering to the subject an herb, an extract thereof, or any combination thereof. In some cases, the herb comprises two or more herbs, extracts thereof, or any combinations thereof in a traditional Chinese medicine formulation. In some cases, the subject is a human subject. In some cases, the human subject is about 1 month to about 12 months old, 1 year to about 20 years, 15 years to about 50 years, 40 years to about 80 years, or about 60 years to about 110 years. In some cases, the human subject has a comorbidity. In some cases, the comorbidity is selected from schematic heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease or any combination thereof. In some cases, comorbidity is a respiratory disease selected from asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, or any combination thereof. In some cases, the subject is a smoker. In some cases, the treating comprises administering a solid formulation to the subject. In some cases, the solid formulation is a powder. In some cases, the solid formulation comprises one or more of remdesivir, chloroquine, lopinavir, ritonavir, favilavir, corticosteroid, interferon-beta, antivirals, vitamin C, azithromycin, amoxicillin, cephalosporin, fluroquinolone, ampicillin, sulbactam, doxycycline, an antibiotic, saline, an herb, an herb extract, a salt of any of these, or a combination thereof. In some cases, the therapeutically effective amount of the allogenic stem cell is formulated as a liquid formulation. In some cases, the liquid formulation is administered by intravenous injection, by inhalation, or a combination thereof. In some cases, the therapeutically effective amount comprises an amount of about 0.1 × 10⁶ cells per kilogram of weight, an amount of 0.1 × 10⁶ cells per kilogram of weight to 1 × 10⁶ cells per kilogram of weight, an amount of about 1 × 10⁶ cells per kilogram of weight, an amount of 1 × 10⁶ cells per kilogram of weight to 5 × 10⁶ cells per kilogram of weight, an amount of about 5 × 10⁶ cells per kilogram of weight, an amount of 5 × 10⁶ cells per kilogram of weight to 10 × 10⁶ cells per kilogram of weight, an amount of about 10 × 10⁶ cells per kilogram of weight, an amount of 10 x 10⁶ cells per kilogram of weight to 20 × 10⁶ cells per kilogram of weight, an amount of about 20 x 10⁶ cells per kilogram of weight, an amount of 20 × 10⁶ cells per kilogram of weight to 100 x 10⁶ cells per kilogram of weight, an amount of about 100 × 10⁶ cells per kilogram of weight, or an amount greater than 100 × 10⁶ cells per kilogram of weight. In some cases, the administering is performed at least once per day, at least twice per day, at least three times per day, or at least 4 times per day. In some cases, the administering is performed for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months 11 months, 1 year, 2 years, 3 years, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months at least 11 months, at least 1 year, at least 2 years, at least 3 years, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 7 days, 1 week to 2 weeks, 2 weeks to 3 weeks, 3 weeks to 4 weeks, 1 month to 2 months, 2 months to 3 months, 3 months to 4 months, 4 months to 5 months, 5 months to 6 months, 6 months to 7 months, 7 months to 8 months, 8 months to 9 months, 9 months, to 10 months, 10 months to 11 months, 11 months to 1 year, 1 year to 2 years, or 2 years to 3 years. In some cases, the allogenic stem cells are harvested mechanically. In some cases, the respiratory damage comprises lung damage, trouble breathing, inflammation, shortness of breath, a cough, wheezing, a productive cough comprising blood, a productive cough comprising mucus, discolored fingernails, decreased blood oxygen level, chest tightness of any combination thereof. In some cases, the viral infection is diagnosed with an antibody diagnostic, quantitative polymerase chain reaction (PCR), real-time reverse transcription PCR, PCR, an enzyme-linked immunosorbent assay (ELISA), a rapid diagnostic test, an imaging method, a general symptom, or any combination thereof. In some cases, the imaging method is an X-ray, computed tomography (CT) scan, a magnetic resonance image (MRI), an ultrasound, or any combination thereof. In some cases, the general symptom is a fever, a cough, a shortness of breath, breathing difficulties, or any combination thereof. In some cases, the administering the therapeutically effective amount of allogenic stem cells results in a change in the respiratory damage. In some cases, a change in the respiratory damage following the administration of the therapeutically effective amount of allogenic stem cells comprises an increased blood oxygen level, reduced cough, decreased wheezing, normal fingernail color, an improved respiratory image relative to an image taken during infection but before administration of stem cells, or any combination thereof. In some cases, the change in the respiratory damage results in at least a partially amelioration of the respiratory damage. In some cases, treatment with the therapeutically effective amount of the allogenic stem cell results in a reduction of inflammation. In some cases, the reduction of inflammation comprises decreased fluid accumulation, reduced swelling, decreased immobility, reduced accumulation of lymphocytes, or any combination thereof. In some cases, the reduction of inflammation comprises decreased TNF-alpha concentration, decreased C-reactive protein concentration, a decreased quantity of overactivated cytokine-secreting immune cells or any combination thereof in the bloodstream of the human. In some cases, the overactivated cytokine-secreting immune cells are T-cells. In some cases, the allosteric stem cells are administered with at least one of the following: fetuin-A, interleukin 37, macrophage colony stimulating factor, serpin A4, syndecan-4, complement component 5a, platelet derived growth factor-AA, thrombospondin-2, adhesion G protein, cystatin-B, galectin- 9, granulysin, lipocalin-2, intracellular adhesion molecule 1. In some cases, after treatment with the therapeutically effective amount of the allogenic stem cell, there is a reduced viral load in the subject. In some cases, the viral load is a Coronavirus viral load. In some cases, the formulation comprises an excipient. In some cases, the excipient is Wharton’s jelly, saline, or any combination thereof. In some cases, the unit dose formulation is contained within a vial. In some cases, the unit dose formulation is stored as a cryogenic composition. In some cases, the cryogenic composition contains a cryoprotectant. In some cases, the cryoprotectant comprises Wharton’s Jelly and saline. In some cases, the viral infection is from the virus SAR-CoV-2 (COVID-19), SARS-COV, MERS-CoV, HKU1, OC43, NL63, 229E or any combination thereof. In some cases, the virus comprises a Coronavirus or a mutated form thereof. In some cases, the virus comprises SAR-CoV-2 (COVID-19) or a mutated form thereof.

INCORPORATION BY REFERENCE

[0006] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede or take precedence over any such contradictory material.

DETAILED DESCRIPTION

[0007] Methods and compositions disclosed herein include treatments and methods of treating subjects having one or more symptoms related to respiratory damage and/or viral infection. In some cases, methods and systems described herein can be used to treat a subject having one or more symptoms associated with and/or caused by a viral infection. For instance, administration of one or more cells (e.g., stem cells, such as mesenchymal stem cells (MSCs)) and/or one or more additional agents described herein (e.g., an antibiotic, an antiviral medication, a steroid, or a corticosteroid) to a subject having one or more symptoms of respiratory damage (e.g., directly or indirectly arising from or associated with a viral infection) can partially or completely ameliorate the one or more symptoms of the respiratory damage, in some embodiments. In some cases, a subject having one or more symptoms associated with a condition having a non-viral cause can be treated using the methods and/or compositions described herein. In some cases, administration of one or more cells (e.g., stem cells, such as mesenchymal stem cells (MSCs)) and/or one or more additional agents described herein (e.g., an antibiotic, an antiviral medication, a steroid, or a corticosteroid) to a subject having one or more symptoms of respiratory damage arising from or associated with emphysema can partially or completely ameliorate the one or more symptoms of the respiratory damage.

[0008] Adult stem cells can be found throughout the body. In some cases, a treatment described herein can comprise one or more allogenic stem cells (e.g., one or more allogenic mesenchymal stem cells (MSCs)). Allogeneic stem cells can be derived from a donor and can be given to a different recipient of the cells. Allogenic stem cells can be undifferentiated cells and can multiply by cell division. Allogenic stem cells can divide indefinitely and can generate many different cell types. In some cases, a treatment described herein can comprise one or more autologous cells (e.g., one or more autologous stem cells, such as mesenchymal stem cells (MSCs). For example, one or more autologous cells (e.g., one or more autologous stem cells, such as MSCs) can be administered to a subject for treating one or more conditions or symptoms described herein (e.g., viral infection, emphysema, lung damage, etc.). A mesenchymal stem cell (MSC) can be one type of allogenic stem cell. In some cases, one or more allogenic cells (e.g., one or more allogenic stem cells, such as MSCs) can be administered to a subject for treating one or more conditions or symptoms described herein (e.g., viral infection, emphysema, lung damage, etc.). MSCs can be of the stromal origin and may differentiate into different types of tissues and cell types, for example, a MSC can differentiate into an osteoblast, a chondroblast, an adipocyte, a myocyte, a neuroectodermal cell, or a hepatocyte. MSCs can be isolated from an umbilical cord, a placenta, an adipose tissue, a lung, teeth, bone marrow, Wharton’s jelly or any combination thereof. In some cases, a method described herein can comprise differentiating one or more stem cells (e.g., one or more MSCs for administration to a subject) toward a cellular lineage (e.g., wherein the cellular lineage is selected from: ectodermal, endodermal, mesodermal or wherein the cellular lineage is selected from osteoblast, chondroblast, adipocyte, myocyte, neuroectodermal, or hepatocyte). In some cases, one or more stem cells, (e.g., one or more MSCs) can be differentiated in culture (e.g., in vitro culture, which may comprise adherent culture on culture plastic, such as tissue culture plastic or culture plastic comprising one or more extracellular matrix proteins, and/or culturing in a bioreactor). In some cases, one or more stem cells (e.g., one or more MSCs) can be differentiated via non-adherent expansion (e.g., via embryoid body formation). In some cases, a method described herein can comprise isolating cells grown ex vivo (e.g., cells grown in culture in vitro). In some cases, cells are not cultured or expanded in vitro. For instance, one or more cells (e.g., one or more MSCs) can be formulated for administration to a subject after isolation (e.g., dissociation from a tissue, for example via mechanical mincing of the tissue), for example, without culturing the cells between isolation and administration. MSCs can be used in clinical therapy to modulate the immune response, provide tropic support, regenerate damaged tissue, or any combination thereof.

[0009] Wharton’s Jelly may be a biological matrix, comprising collagen and glucosaminoglycans, and found in umbilical cords. Wharton’s Jelly can be harvested by enzymatic or mechanical methods. The jelly may comprise various cell types, mucopolysaccharides, proteins, glycoproteins, growth factors, cytokines or any combination thereof. In some embodiments, Wharton’s Jelly can include an epithelial cell, an epidermal cell, a fibroblast, an immune cell, a stem cell or any combination thereof. For example, Wharton’s Jelly can be a rich source of MSCs. In some cases, Wharton’s Jelly can contain up to 20% MSC. [0010] In some embodiments, viable MSCs can be isolated from different sources, for example, an umbilical cord, with a tissue mincer, a chemical, an enzymatic, a mechanical disruption or any combination thereof. In some cases, an MSC can be a primary cell or an immortalized cell (e.g., an immortalized MSC). In some embodiments, mechanical disruption may be a tissue mincer. In some cases, the use of a tissue mincer can comprise using a manual tissue mincer (e.g., a pair of scissors) or a mechanical tissue mincer (e.g., an automatic tissue mincer, such as a tissue homogenizer). In some embodiments, a mechanical disruption can reduce the solid tissue of the umbilical cord to pieces of between about 0.1 grams to about 10 grams. The umbilical cord tissue pieces can be combined with an amount of saline, at a ratio of grams tissue: milliliters saline of from about 1 : 100 to about 1 :2, in one embodiment about 1 gram of tissue can be combined with about 5 ml of saline (i.e. 1:5). In some embodiments, the saline can be a solution ofNaCl of between 0.1 and 23%, in one embodiment, the saline can be about a 0.9% solution. In some embodiments, the Wharton’s Jelly may be subjected to further processing after processing with the tissue mincer. In some embodiments the Wharton’s Jelly can be separated from solid tissue and other larger pieces of umbilical cord by filtering through, for example, a filter of at least about 100 micrometer (μm) pore size filter. In some embodiments, the Wharton’s Jelly can be filtered through a filter having a pore size less than about 100 μm, 95 μm, 90 μm, 85 μm, 80 μm, 75 μm, 70 μm, 65 μm, 60 μm, 55 μm, 50 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, or 5 μm, or greater than about 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, or 95 μm. [0011] In some embodiments, the Wharton’ s Jelly can comprise one or more of a mammalian cell, a protein, a peptide, and an extracellular matrix. In some embodiments, the Wharton’s Jelly can comprise a population ofMSCs at a concentration of between about 0.1 ×10⁶ cells/mL and 20 ×10⁶ cells/mL, In some embodiments, the Wharton’s Jelly can comprise about 5-40% MSCs of the total population of cells, in some embodiments the amount of MSCs in Wharton’s Jelly, relative to all the cells, can be about 20%. In some embodiments, MSCs can express CD73, CD90, CD105, or any combination thereof. In some embodiments, MSCs can express TNF-α receptor type 1. In some embodiments, one or more MSCs may not substantially express CD11, CD 14, CD 19, CD34, CD45, HLA-DR, or any combination thereof (e.g., wherein the one or more MSCs express CD11, CD 14, CD 19, CD34, CD45, and/or HLA-DR at a level that is statistically similar to and/or does not have a higher median level of expression than a control cell population, such as a cell population known to express phenotypically insignificant levels of the marker(s)). In some embodiments, viable MSCs are plastic adherent. A population of cells can be positive for a specific marker if between about 30% and 100% of the cells express the marker, for example, greater than about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, and less than about 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, or 35%. A population of cells can be negative for a specific marker if between about 70% and 0% of the cells express the marker, for example less than about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%, and greater than about 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65%. In some embodiments, a positive marker can be expressed by more than 80% of the population and a negative marker can be expressed by less than about 20% of the population. In some embodiments, a cell that may be negative for a given marker, can have a level of staining that may be above zero, but less than what may be deemed the level of background for a given ceil with a given marker. In some embodiments, the MSCs are not expanded in vitro. In some embodiments, expansion (e.g., culture) of all or a portion of a population ofMSCs used in a treatment described herein in vitro (e.g., on culture plastic or a culture plastic coated with one or more extracellular matrix molecules) has been disallowed.

[0012] In some embodiments, the MSCs can be cryopreserved. In some embodiments, cryopreservation can occur at temperatures less than about -20 °C to greater than about -140 °C. In some embodiments, cryopreservation can include a composition. In some embodiments, the cryopreservation compositions may include a concentration of DMSO between about 0% to about 30%, a concentration of human serum albumin between about 0.1 and about 10%, or any combination thereof. In some embodiments, the cryopreservation composition can include saline, Wharton’s jelly, or any combination thereof. In some embodiments, the cryopreservation composition can include DMSO, albumin, saline, Wharton’s jelly, or any combination thereof. In some embodiments, the MSCs can be in a vial. In some embodiments, the vial can be glass, plastic, metal, or any combination thereof.

[0013] Methods of Treatment

[0014] The terms “administer,” “administering”, “administration,” and the like, as used herein, can refer to methods that can be used to enable delivery of MSCs or MSCs formulations to the desired site of biological action. Delivery can include direct application to the affect tissue or region of the body. Delivery can include a parenchymal injection, an intra-thecal injection, an intra-ventricular injection, or an intra-ci sternal injection. A composition provided herein can be administered by any method. A method of administration can be by intravenous injection, intraarterial injection, intracerebroventricular injection, intraci sternal injection, intramuscular injection, intraorbital injection, intraparenchymal injection, intraperitoneal injection, intraspinal injection, intrathecal injection, intraventricular injection, stereotactic injection, subcutaneous injection, or any combination thereof. Delivery can include parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular or infusion), oral administration, inhalation administration, intraduodenal administration, rectal administration. In some embodiments, delivery can include topical administration (such as a lotion, a cream, a gel, a liquid, a solid, a powder, an ointment) to an external surface of a surface, such as a skin. In some cases, a liquid formulation can be converted (e.g., dried, for example, by a process comprising freeze-drying or other means such as atomization) into a solid (e.g., a powder). In some cases, a treatment (e.g., which can be administered to a subject, such as a subject having or suspected of having a viral infection) comprises one or more MSCs and/or one or more additional agents, such as azithromycin, amoxicillin, cephalosporin, fluroquinolone, ampicillin, sulbactam, doxycycline, an antibiotic, remdesivir, chloroquine, lopinavir, ritonavir, favilavir, corticosteroid, interferon-beta, antivirals, vitamin C, a salt of any of these, or any combination. In some cases, a treatment (e.g., comprising one or more of azithromycin, amoxicillin, cephalosporin, fluroquinolone, ampicillin, sulbactam, doxycycline, an antibiotic, remdesivir, chloroquine, lopinavir, ritonavir, favilavir, corticosteroid, interferon-beta, antivirals, vitamin C, a salt of any of these, or any combination thereof) can be in the form of a lyophilized solid (e.g., a lyophilized powder). In some cases, a solid or powder formulation described herein (e.g., lyophilized solid or lyophilized powder) can be hydrated or reconstituted at a desired concentration in a liquid to produce a liquid formulation (e.g., for injection or oral administration). In some cases, a solid or powder formulation described herein (e.g., a lyophilized solid or lyophilized powder) can be delivered via inhalation. In some instances, a subject can administer the composition in the absence of supervision. In some instances, a subject can administer the composition under the supervision of a medical professional (e.g., a physician, nurse, physician’s assistant, orderly, hospice worker, or a combination thereof). In some embodiments, a medical professional can administer the composition.

[0015] As used herein, the term “treatment” or “treating” of a viral infection can comprise causing a change in (e.g., reducing) the frequency or severity of symptoms. In some cases, treating a subject (e.g., who has a viral infection) can comprise at least partially ameliorating (e.g., repairing) respiratory damage, elimination of symptoms, elimination of a symptom’s underlying cause, elimination of the infectious disease, improvement of damage, remediation of damage, or any combination thereof. For example, treatment of a viral infection can include, for example, relieving the cough experienced by a subject (e.g., a human male subject or a human female subject) having a viral infection (e.g., Coronavirus infection), or causing the regression or disappearance of a viral infection (e.g., a Coronavirus infection). In some cases, treatment of a male subject can be different than treatment of a female subject having a same or similar viral infection (e.g., based on gender-related presentation of symptoms and/or gender-based response to treatment). In some embodiments, treatment can include an improved respiratory diagnostic image relative to a diagnostic image taken during infection but before administration of the stem cells. In some embodiments, treatment can reduce proinflammatory cytokines, for example, TNF-α, IL-Ib, IL-6, IL-2, IL-7, GSCF, IP10, MCP1, MIP1A, or any combination thereof. In some embodiments, treatment can reduce C-reactive protein. In some embodiments, treatment can reduce overactivated immune cells, for example, T-cells, macrophages, neutrophils, NK cells, peripheral blood mononuclear cells (PBMCs) or any combination thereof. Treating can also include: reduced malaise, cessation of viral infection side effects, abatement of a viral infection, or any combination thereof.

[0016] Disclosed herein are methods of treating a condition by administering MSCs as described herein. In some embodiments, the MHCs can be administered during the infection. In some embodiments, the MHCs can be administered before the infection. In some embodiments, the MHCs can be administered after the infection. In some embodiments the MHCs can be administered before, during, and after an infection. In some embodiments representative daily intravenous, or injection dosages are from about 0.1 × 10⁶ cells per kilogram of weight to about 1. × 10⁶ cells per kilogram of weight, from about 1 × 10⁶ cells per kilogram of weight to about 10 x 10⁶ cells per kilogram of weight, from about 10 × 10⁶ cells per kilogram of weight to about 100 x 10⁶ cells per kilogram of weight, or from about 100 × 10⁶ cells per kilogram of weight to about 1000 × 10⁶ cells per kilogram of weight per day of the MSC. These ranges of dosage amounts represent total dosage amounts of the active ingredient per day for a given patient. In some embodiments, a daily administered dose can be less than about: 1000 × 10⁶ cells per kilogram of weight, 100 × 10⁶ cells per kilogram of weight, 10 × 10⁶ cells per kilogram of weight, 1 × 10⁶ cells per kilogram of weight, 0.1 × 10⁶ cells per kilogram of weight, or 0.01 × 10⁶ cells per kilogram of weight per day of the MSCs. In some embodiments, a daily administered dose can be at least about: 1000 × 10⁶ cells per kilogram of weight, 100 × 10⁶ cells per kilogram of weight, 10 × 10⁶ cells per kilogram of weight, 1 × 10⁶ cells per kilogram of weight, 0.1 × 10⁶ cells per kilogram of weight, or 0.01 × 10⁶ cells per kilogram of weight per day of the MSC. In some embodiments the treatment can be given once, twice, three, or four times in a 24 hour period. In some embodiments the treatment with MSC cells can last about or at least: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days. In some embodiments the treatment with MSCs can last about or at least: 1 week, 2 weeks, 3 weeks, 4 weeks. In some embodiments the treatment with MSCs can last about or at least: 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years or 10 years.

[0017] In some embodiments, the treatment of MSCs can be administered with a second therapy that can comprise one or more agents selected from remdesivir, chloroquine, lopinavir, ritonavir, favilavir, corticosteroid, interferon-beta, antivirals, vitamin C, azithromycin, amoxicillin, cephalosporin, fluroquinolone, ampicillin, sulbactam, doxycycline, an antibiotic, an antifungal, an antimalarial, a salt of any of these, or any combination thereof. In some embodiments, the treatment of MSCs can be oxygen, intravenous saline, or any combination thereof. In some embodiments, a second therapy can comprise an anticancer drug, chemotherapy, radiation, a bone marrow transplantation, immunotherapy, a hormone therapy, a cryotherapy, a surgical procedure or any combination thereof. A second therapy can comprise administration of a muscle relaxant, an anti-depressant, a steroid, an opioid, a cannabis-based therapeutic, acetaminophen, a non-steroidal anti-inflammatory, a neuropathic agent, a cannabis, a progestin, a progesterone, or any combination thereof. A second therapy can include a non-steroidal anti- inflammatory can comprise naproxen, ibuprofen, a COX-2 inhibitor, or any combination thereof. A second therapy can comprise administration of a biologic agent, cellular therapy, regenerative medicine therapy, a tissue engineering approach, a stem cell transplantation or any combination thereof. A second therapy can comprise a medical procedure. A second therapy can comprise an herb, an extract thereof of any combination thereof. The herb or herb extract can be one of traditional Chinese medication, for example, astragalus, ginkgo biloba, red yeast rice, cinnamon, ginger, ginseng, goto kola, yu xing cao, monkshood rood, birth works, cayenne pepper, Chinese kabootar, cocklebur fruit, crow differ, croton seed, dioscorea root, rhubarb, cardamom fruit, thunder god vine, insects, fungi, marine life, minerals, mammals, reptiles, amphibians, or any combination thereof.

[0018] In some embodiments a subject can be a human. In some embodiments, a subject can have or can be suspected of having a disease or condition. The subject can be a patient, such as a patient being treated for a condition or a disease, such as a heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, Coronavirus infection, pneumonia, pleural effusion or any combination thereof. In some embodiments the subject can have one or more symptoms of respiratory damage. In some cases, respiratory damage can comprise lung damage, trouble breathing, inflammation, shortness of breath, a cough, wheezing, a productive cough comprising blood, a productive cough comprising mucus, discolored fingernails, decreased blood oxygen level, chest tightness, or any combination thereof. In some cases, the subject can have and/or be suspected of having and/or be at risk of having acute respiratory distress syndrome (ARDS). In some cases, ARDS can result from an inflammatory response in a subject’s body (e.g., in response to a viral infection). In some cases, ARDS can develop from a non-viral cause. In some cases, ARDS can arise from a condition such as emphysema, which can be caused by smoking. In some cases, a subject can be identified (e.g., alone or in combination with one or more additional indications, such as family history, a viral infection, and/or heart disease) as a candidate for treatment with one or more methods or compositions described herein on the basis of being a smoker (e.g., of tobacco products) or having a history of smoking. In some cases, ARDS can be caused by overactivated immune cells, such as overactivated T-cells. In some cases, ARDS can result from cytokine storm (e.g., which may result from a viral infection) and/or be identified by symptoms of cytokine storm in a subject (e.g., increased cytokine levels in the blood and/or increased activation of immune cells, such as immune cells in the blood). In some cases, ARDS can result in excess fluid accumulation in the lungs and/or damage to the lungs (e.g., resulting from fluid accumulation in the lungs). In some cases, the presence of ARDS in a subject can be determined via measurement of blood oxygenation and/or via imaging (e.g., X-ray imaging or computer tomography (CT) imaging). A subject can be predisposed to a risk of developing a condition or a disease such as a respiratory disease. A subject can be in remission from a condition or a disease, such as a cancer patient. A subject can be healthy.

[0019] In some embodiments, a composition or formulation can be a liquid, a solid, an aerosol, a powder, or any combination thereof. In some embodiments, the composition or formulation can include an excipient. Excipients can include, but are not limited to one or more of: Wharton’s jelly, saline, water, a fluidizer, a lubricant, an adhesion agent, a surfactant, an acidifying agent, an alkalizing agent, an agent to adjust pH, an antimicrobial preservative, an antioxidant, an anti- static agent, a buffering agent, a chelating agent, a humectant, a gel-forming agent, or a wetting agent. Excipients can also include a coloring agent, a coating agent, a sweetening agent, a flavoring and perfuming agent or a masking agent. A composition and formulation can include a therapeutic agent with an individual excipient or with multiple excipients in any suitable combination, with or without a carrier.

[0020] A therapeutically effective amount can refer to the amount of MSCs with or without additional agents that can be effective to achieve its intended purpose. Individual patient needs may vary. Generally, the dosage required to provide an effective amount of the compound, salt thereof, or composition containing one or both of these, and which can be adjusted by one of ordinary skill in the art, will vary, depending on the age, health, physical condition, sex, weight, extent of the dysfunction of the recipient, frequency of treatment and the nature and scope of the dysfunction. Dosages can be in unit dose form.

[0021] In some cases, administering MSCs as described herein can be used to prevent or treat diseases associated with or caused by a virus (e.g., a Coronavirus). Such diseases can include, for example, a cough, a fever, malaise, myalgia, fatigue, difficult breathing, a runny nose, a sore throat, nasal congestion, a headache, diarrhea, acute respiratory distress syndrome (ARDS), a secondary infection or any combination thereof. In some embodiments, the secondary infection can be a bacterial infection, a viral infection, a fungal infection, an infectious disease, or any combination thereof. A coronavirus infection can be caused by alpha coronavirus, beta coronavirus, gamma coronavirus, delta coronavirus, 229E coronavirus, NL63 coronavirus, OC43 coronavirus, HKU1 coronavirus, MERS-CoV, SARS-CoV, SARS-CoV-2 (COVID-19), or any combination of these. In some embodiments, a coronavirus infection can be diagnosed with an antibody diagnostic, polymerase chain reaction (PCR), quantitative polymerase chain reaction (qPCR), real-time reverse transcription PCR, an enzyme-linked immunosorbent assay (ELISA), a rapid diagnostic test, IgG, IgM, IgA, an imaging method, a general symptom or any combination thereof. In some embodiments, the imaging method can be an X-ray, a computed tomography (CT) scan, a magnetic resonance image (MRI), an ultrasound, or any combination thereof. In some embodiments the general symptom can be a cough, shortness of breath, breathing difficulties, or a combination thereof.

[0022] In some cases, administering MSCs as described herein can be used for patients with comorbidities. Such comorbidities can include, for example, hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, dementia including Alzheimer's disease, immunodeficiency, premature labor, Parkinson's disease, multiple sclerosis, dysmenorrhoea, benign prostatic hyperplasis (BPH), bladder outlet obstruction, incontinence, conditions of reduced blood vessel patency, e.g., postpercutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, respiratory disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, allergic rhinitis, glaucoma, malignancies and diseases characterized by disorders of gut motility, e.g, irritable bowel syndrome (IBS), rheumatoid arthritis, systemic lupus erythematosus, psoriasis, other autoimmune diseases, Huntington's chorea, and Amyotrophic lateral sclerosis (ALS) or any combination thereof. Treatment of comorbidities can be accomplished by administering to a patient in need thereof a therapeutically effective amount of the compound or composition described herein.

[0023] Also disclosed herein are methods of making a composition described herein. A method of making a composition can comprise contacting a cell as described herein other ingredients as described herein (e.g. a carrier, diluent, excipient, etc.).

[0024] Unless otherwise indicated, open terms for example “contain,” “containing,” “include,” “including,” and the like mean comprising.

[0025] While exemplary embodiments have been shown and described herein, such embodiments are by way of example only. Numerous variations, changes, and substitutions can be performed on the exemplary embodiments. It should be understood that various alternatives to the embodiments described herein may be employed.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for treating one or more symptoms in a subject comprising: administering a therapeutically effective amount of allogenic stem cells to the subject to treat the one or more symptoms, wherein

(i) the one or more symptoms comprise respiratory damage,

(ii) the allogenic stem cells are from at least in part Wharton’s jelly, and

(iii) the allogenic stem cells are administered in a formulation in unit dose form.

2. The method of claim 1, wherein the one or more symptoms are at least in part produced from or occurring as a result of a viral infection.

3. The method of claim 1, wherein the one or more symptoms are at least in part produced from or occurring as a result of a non-viral cause.

4. The method of claim 1, wherein the subject has emphysema.

5. The method of claim 1, wherein the allogenic stem cells comprise mesenchymal stem cells (MSCs).

6. The method of claim 2, wherein the MSCs are not expanded in vitro.

7. The method of claim 2, wherein the MSCs express CD73, CD90, CD105, or any combination thereof.

8. The method of claim 2, wherein the MSCs do not substantially express CD14, CD34, CD45, HLA-DR, CD 19, or any combination thereof.

9. The method of claim 1, wherein the allogenic stem cells are harvested mechanically.

10. The method of claim 2, wherein the administering is performed during onset of a viral infection.

11. The method of claim 2, wherein the administering is performed after onset of a viral infection.

12. The method of claim 2, wherein the administering is performed before and after onset of a viral infection.

13. The method of any one of claims 1-9, further comprising administering to the subject remdesivir, chloroquine, lopinavir, ritonavir, favilavir, corticosteroid, interferon-beta, antivirals, vitamin C, a salt thereof, or any combination thereof.

14. The method of any one of claims 1-9, further comprising administering to the subject oxygen, saline, or any combination thereof.

15. The method of any one of claims 1-9, further comprising administering to the subject azithromycin, amoxicillin, cephalosporin, fluroquinolone, ampicillin, sulbactam, doxycycline, an antibiotic, a salt of any of these, or any combination thereof.

16. The method of any one of claims 1-9, further comprising administering to the subject an herb, an extract thereof, or any combination thereof.

17. The method of claim 166, wherein the herb comprises two or more herbs, extracts thereof, or any combinations thereof in a traditional Chinese medicine formulation.

18. The method of claim 1, wherein the subject is a human subject.

19. The method of claim 18, wherein the human subject is about 1 month to about 12 months old, 1 year to about 20 years, 15 years to about 50 years, 40 years to about 80 years, or about 60 years to about 110 years.

20. The method of claim 18, wherein the human subject has a comorbidity.

21. The method of claim 20, wherein the comorbidity is selected from schematic heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease or any combination thereof.

22. The method of claim 20, wherein the comorbidity is a respiratory disease selected from asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, or any combination thereof.

23. The method of claim 1, wherein the subject is a smoker.

24. The method of claim 1, wherein the therapeutically effective amount of the allogenic stem cell is formulated as a liquid formulation.

25. The method of claim 24, wherein the liquid formulation is administered by intravenous injection, by inhalation, or a combination thereof.

26. The method of claim 1, wherein the treating comprises administering a solid formulation to the subject.

27. The method of claim 26, wherein the solid formulation is a powder.

28. The method of claim 26 or claim 27, wherein the solid formulation comprises one or more of remdesivir, chloroquine, lopinavir, ritonavir, favilavir, corticosteroid, interferon- beta, antivirals, vitamin C, azithromycin, amoxicillin, cephalosporin, fluroquinolone, ampicillin, sulbactam, doxycycline, an antibiotic, saline, an herb, an herb extract, a salt of any of these, or a combination thereof.

29. The method of claim 1, wherein the therapeutically effective amount comprises an amount of about 0.1 × 10⁶ cells per kilogram of weight, an amount of about 1 × 10⁶ cells per kilogram of weight, an amount of about 5 × 10⁶ ceils per kilogram of weight, an amount of about 10 × 10⁶ cells per kilogram of weight, an amount of about 20 × 10⁶ cells per kilogram of weight or about 100 × 10⁶ ceils per kilogram of weight.

30. The method of claim 1, wherein the administering is performed at least once per day, at least twice per day, at least three times per day, or at least 4 times per day.

31. The method of claim 30, wherein the administering is performed for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 1 day to 2 days, 2 days to 3 days, 3 days to 4 days, 4 days to 5 days, 5 days to 7 days, 1 week to 2 weeks, 2 weeks to 3 weeks, 3 weeks to 4 weeks, 1 month to 2 months, 2 months to 3 months, 3 months to 4 months, 4 months to 5 months, 5 months to 6 months, 6 months to 7 months, 7 months to 8 months, 8 months to 9 months, 9 months, to 10 months, 10 months to 11 months, 11 months to 1 year, 1 year to 2 years, or 2 years to 3 years.

32. The method of claim 1, wherein the allogenic stem cells are harvested mechanically.

33. The method of claim 1, wherein the respiratory damage comprises lung damage, trouble breathing, inflammation, shortness of breath, a cough, wheezing, a productive cough comprising blood, a productive cough comprising mucus, discolored fingernails, decreased blood oxygen level, chest tightness of any combination thereof.

34. The method of claim 1, wherein the viral infection is diagnosed with an antibody diagnostic, quantitative polymerase chain reaction (PCR), real-time reverse transcription PCR, PCR, an enzyme-linked immunosorbent assay (ELISA), a rapid diagnostic test, an imaging method, a general symptom, or any combination thereof.

35. The method of claim 34, wherein the imaging method is an X-ray, computed tomography (CT) scan, a magnetic resonance image (MRI), an ultrasound, or any combination thereof.

36. The method of claim 34, wherein the general symptom is a fever, a cough, a shortness of breath, breathing difficulties, or any combination thereof.

37. The method of claim 1, wherein the administering the therapeutically effective amount of allogenic stem cells results in a change in the respiratory damage.

38. The method of claim 37, wherein a change in the respiratory damage following the administration of the therapeutically effective amount of allogenic stem cells comprises an increased blood oxygen level, reduced cough, decreased wheezing, normal fingernail color, an improved respiratory image relative to an image taken during infection but before administration of stem cells, or any combination thereof.

39. The method of claim 37 or claim 38, wherein the change in the respiratory damage results in at least a partially amelioration of the respiratory damage.

40. The method of claim 1, wherein after treatment with the therapeutically effective amount of the allogenic stem cell results in a reduction of inflammation.

41. The method of claim 40, wherein the reduction of inflammation comprises decreased fluid accumulation, reduced swelling, decreased immobility, reduced accumulation of lymphocytes, or any combination thereof.

42. The method of claim 40, wherein the reduction of inflammation comprises decreased TNF-alpha concentration, decreased C-reactive protein concentration, a decreased quantity of overactivated cytokine-secreting immune cells or any combination thereof in the bloodstream of the human.

43. The method of claim 42, wherein the overactivated cytokine-secreting immune cells are T-cells.

44. The method of claim 1, wherein the allosteric stem cells are administered with at least one of the following: fetuin-A, interleukin 37, macrophage colony stimulating factor, serpin A4, syndecan-4, complement component 5a, platelet derived growth factor-AA, thrombospondin-2, adhesion G protein, cystatin-B, galectin-9, granulysin, lipocalin-2, intracellular adhesion molecule 1.

45. The method of claim 2, wherein after treatment with the therapeutically effective amount of the allogenic stem cell there is a reduced viral load in the subject.

46. The method of claim 45, wherein the viral load is a Coronavirus viral load.

47. The method of claim 1, wherein the formulation comprises an excipient.

48. The method of claim 47, wherein the excipient is Wharton’s jelly, saline, or any combination thereof.

49. The method of claim 1, wherein the unit dose formulation is contained within a vial.

50. The method of claim 1, wherein the unit dose formulation is stored as a cryogenic composition.

51. The method of claim 50, wherein the cryogenic composition contains a cryoprotectant.

52. The method of claim 51, wherein the cryoprotectant comprises Wharton’s Jelly and saline.

53. The method of claim 2, wherein the viral infection is from the virus SAR-CoV-2 (COVID-19), SARS-COV, MERS-CoV, HKU1, OC43, NL63, 229E or any combination thereof.

54. The method of claim 2, wherein the viral infection comprises infection by a Coronavirus or a mutated form thereof.

55. The method of claim 2, wherein the viral infection comprises infection by SAR-CoV-2 (COVID-19) or a mutated form thereof.