EP4240384A1 - Verfahren zur reduktion der population mindestens einer intestinalen und/oder gastrointestinalen bakterienart umfassend bakteriophagen sowie bakteriophagen und deren verwendung - Google Patents
Verfahren zur reduktion der population mindestens einer intestinalen und/oder gastrointestinalen bakterienart umfassend bakteriophagen sowie bakteriophagen und deren verwendungInfo
- Publication number
- EP4240384A1 EP4240384A1 EP21799202.3A EP21799202A EP4240384A1 EP 4240384 A1 EP4240384 A1 EP 4240384A1 EP 21799202 A EP21799202 A EP 21799202A EP 4240384 A1 EP4240384 A1 EP 4240384A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- disorder
- nucleic acid
- intestinal
- bacterial species
- bacteriophage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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- C—CHEMISTRY; METALLURGY
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Definitions
- the invention relates to a method for reducing the population of at least one intestinal and/or gastrointestinal bacterial species and bacteriophages and their use according to the preamble of the independent claims.
- the microbiome i.e. the entirety of all microorganisms that colonize the gastrointestinal tract, is involved in numerous other metabolic processes in addition to digestion and the formation of the immune system.
- One of the reasons for this is that around a third of all metabolic products in human and/or animal blood come from the microbes in the body. It is therefore not surprising that more and more studies show that the microbiome can have an influence on various diseases that are far from intestinal and/or gastrointestinal disorders. Studies have shown that the intestinal flora can influence the thinking, feeling, mood and/or psyche of an organism the exact connections of this so-called "gut-brain axis" are not yet known.
- the disadvantage here is that the bacteria are also affected which have a positive benefit for humans or animals or live together symbiotically with them, which can lead to consequential damage to humans, animals and/or the environment. It is conceivable that this can lead to a shift in the balance of the microbiome in favor of pathogenic microorganisms (e.g. bacteria and/or fungi), which can lead to a condition lasting several months or years with often serious consequences.
- pathogenic microorganisms e.g. bacteria and/or fungi
- chemical substances that are used as antibiotics can interact with physiological metabolic processes and, among other things, cause allergies to the chemical substance and the consequences of an allergic reaction resulting from it, including allergic shock syndrome and/or the development of various intolerances.
- the invention has therefore set itself the task of bacteriophages and a method for reducing the population tion to provide at least one intestinal and / or gastrointestinal bacterial species in order to avoid the above-mentioned disadvantages of the prior art and which is characterized by high effectiveness, specificity, tolerability and / or reliability, as well as simple, low-error, time- and cost-efficient application.
- a method for reducing the population of at least one intestinal and/or gastrointestinal bacterial species comprises the following steps: a) providing a biological sample which comprises bacteria of at least one intestinal and/or gastrointestinal bacterial species, the intestinal and/or gastrointestinal bacterial species directly or indirectly affects a mental, neurodegenerative and/or neurological disease and/or disorder of a host organism; and b) providing bacteriophages of at least one bacteriophage species which are specific for the intestinal and/or gastrointestinal bacterial species and which comprise at least one nucleic acid functionally linked to a promoter and/or a regulatory element, the nucleic acid being selected from the group comprising :i.
- nucleic acid sequence encoding at least one antibacterial nucleic acid molecule
- ii a nucleic acid sequence which encodes a nucleic acid molecule which is at least 50% identical to the nucleic acid molecule which is encoded by the nucleic acid sequences from i); and iii. a nucleic acid sequence encoding at least one antibacterial polypeptide
- IV a nucleic acid sequence encoding a polypeptide that is at least 50% identical to a polypeptide encoded by the nucleic acid sequences of iii); and V.
- nucleic acid sequence for a fragment of a nucleic acid from i), ii), iii) or iv), wherein the fragment encodes a nucleic acid molecule or a polypeptide; and c) contacting and incubating the biological sample with the bacteriophage, wherein the incubating is carried out until at least a 70% reduction in the population of the intestinal and/or gastrointestinal bacterial species is achieved.
- the method according to the invention is based on the basic idea that by using bacteriophages specific for the at least one intestinal and/or gastrointestinal bacterial species, it is possible to reliably, quickly, easily, specifically and permanently increase the population of this at least one intestinal and/or gastrointestinal bacterial species to reduce. It has been found that due to the simultaneous host dependency, other organisms, such as fungi, bacteria, viruses or the like, and/or cells of multicellular tissues and/or organisms advantageously remain unaffected, so that no damage, impairment and/or disruption occurs. Due to the host dependency of the bacteriophages, the method according to the invention can be repeated at any time without any resistance developing.
- simultaneous host dependence exists when, in the absence of the respective intestinal and/or gastrointestinal bacterial species within the biological sample, there is no reduction in another bacterial species within the biological sample for which the bacteriophage is not specific.
- This also applies to organs and/or tissues of the host organism, ie the human and/or animal organism.
- population is known to a person skilled in the art and generally relates to all individuals of the same species that occur in a specific area or in a specific area of the environment. In the context of the invention, the population relates to all of the bacteria of at least one intestinal and/or gastrointestinal bacterial species.
- bacteria and “bacteria” are understood by a person skilled in the art as interchangeable synonyms and relate to the representatives of one or more types of bacteria.
- intestinal and/or gastrointestinal bacterial species is known to a person skilled in the art and relates to at least one species of bacteria, preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more types of bacteria which can occur and/or reside within the gastrointestinal tract of the human and/or animal organism, such as for example in the stomach and/or in the intestine.
- the intestinal and / or gastrointestinal bacterial species influences the host organism directly or indirectly due to their way of life, for example through their molecular metabolism and / or their interaction with other bacterial species, fungi and / or cells, so that a psychological, neurodegenerative and / or neurological disease and/or disorder is initiated, favored, manifested and/or increased.
- a direct or indirect influence on the host organism is known to a person skilled in the art. For example, they can directly influence the host organism by destroying the tissue of the host organism or by sending out at least one messenger substance. Farther they can influence the host organism indirectly, for example by influencing the metabolism, other microorganisms or other processes of the host organism and/or by changing the composition of the intestinal flora. Furthermore, the person skilled in the art understands that although the corresponding type of bacteria in this context does not itself have to cause a direct effect in the organism, it can, however, oppose the growth, the way of life and/or the survival of an opposing type of bacteria and thus indirectly have an effect on has the host organism.
- the intestinal and/or gastrointestinal bacterial species is not exclusively selected from: Acinetobacter, Actinobacterium, Actinomyces, Actinomycineae, Alistipes, Acidaminococcaceae, Bacillus, Bacteroides, Bacteroidetes, Bartonella, Bifidobacterium, Blautia, Bordetella, Borrelii, Brucella, Bulleidia, Citrobacter, Campylobacter, Chlamydia , Christensenellaceae, Clostridium, Coprococcus, Corynebacteria, Coriobacterium, Deltaproteobacteria, Desulfovibrio, Dialister, Ehrlichia, Enterobacter, Enterobacterium, Enterococcus, Erysipelotrichia, Erwinia, Escherichia, Eubacterium, Faecalibacterium, Firmicutes, Flavonifractor, Francisella, Fusobacterium, Helicobacter, Hemophilus,
- the intestinal and/or gastrointestinal bacterial species is not exclusively selected from: Acinetobacter baumannii, Bacillus cereus, Bacillus anthracis, Bacillus subtilis, Bacteroides faecichinchillae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteriodes vulgatus, Bartonella henselae, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium lactis, Bifidobacterium weanthorophersis, Blautiaotorophersis, Blautiaotorophersis hydrogen Borrelia recurrentis, Borrelia hermsii, Borrelia turicatue, Borrelia burgdorferi, Campylobacter jejuni, Citrobacter fruendii, Citrobacter rodent
- EHEC, EIEC, ET EC Eubacterium ventriosum, Erysipelothrix rhusiopathiae, Faecalibacterium prausnitzii, Firmicutes phyla, Flavo- nifractor plautii, Francisella tularensis, Helicobacter pylori, Hemophilus influenzae, Hemophilus parainfluenzae, Hemophilus aegyptus, Klebsiella pneumoniae, Lactobacillus acidophilus, Lactobacillus bulga- ricus, Lactobacillus brevis, Lactobacillus casei, Lactobacillus farcimi- nis, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactococcus
- biological sample comprising bacteria of at least one intestinal and/or gastrointestinal bacterial species.
- biological sample relates to a material from a human and/or animal organism and/or a material which has come into at least brief contact with a human and/or animal organism. It has been recognized as essential that the biological sample comprises bacteria of at least one intestinal and/or gastrointestinal bacterial species, preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20 or more bacterial species.
- samples are known to a person skilled in the art, such as cell- and nucleated (DNA- and/or RNA-containing) samples from, inter alia, saliva, urine, blood, stool, sweat, cellular tissue, organ puncture, organs, parts of organs, Whole organisms (including dead ones), soil samples, water samples or similar samples.
- DNA- and/or RNA-containing samples from, inter alia, saliva, urine, blood, stool, sweat, cellular tissue, organ puncture, organs, parts of organs, Whole organisms (including dead ones), soil samples, water samples or similar samples.
- bacteriophages of at least one bacteriophage species that are specific for the at least one intestinal and/or gastrointestinal bacterial species.
- the term "bacteriophage” or "bacteriophage species” is understood and relevant to a person skilled in the art infectious organic structures that can spread outside cells and multiply inside a cell.
- the cells serve as a host and in the case of bacteriophages are essentially bacteria, with bacteriophages having a pronounced host specificity, ie in other words they are specific for at least one bacterial species and thus only those bacteria for which they are specific for the propagation and use propagation.
- the bacteriophages used for the method according to the invention comprise at least one nucleic acid functionally linked to a promoter and/or a regulatory element or have a promoter and/or a regulatory element in combination with a nucleic acid, the nucleic acid encodes either an antibacterial nucleic acid molecule, a bacterial polypeptide and/or a fragment thereof.
- the bacteriophages preferably comprise a nucleic acid with at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more promoters and /or regulatory elements.
- the nucleic acid sequences which code for promoters or regulatory sequences are sufficiently known to the person skilled in the art.
- nucleic acids “genes”, “DNA”, “RNA”, “mRNA”, “cRNA”, “miRNA” and the compositions “nucleic acid sequence” and “nucleic acid molecule” can be used as interchangeable synonyms for each other to denote deoxyribonucleotides or ribonucleotides and polymers thereof, either single or double stranded.
- promoter and “regulatory sequence” or “regulatory element” are also understandable to the person skilled in the art and relate to nucleic acid sequences of the DNA which enable and/or increase the expression, ie the transcription of a gene into mRNA.
- regulatory elements can, for example, cer elements, ie binding sites for growth factors, hormones, oncogenes and/or the like.
- polypeptide polypeptide
- amino acids amino acids
- protein protein
- Naturally occurring amino acids are those encoded by the genetic code and those amino acids that can later be modified.
- Polypeptides can be present as reserve substances, as transport and/or signaling molecules, as structural molecules, as protective and/or defense molecules and/or as metabolically active molecules and can perform various functions inside and/or outside a cell or in the organism.
- polypeptides can have an antibacterial effect and thus counteract the way of life of the bacteria due to their properties or functions.
- At least one antibacterial nucleic acid molecule, an antibacterial polypeptide and/or a fragment thereof is provided; the bacteriophages can preferably also have 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more encode antibacterial nucleic acid molecules, antibacterial polypeptides and/or fragments thereof.
- Antibacterial nucleic acid molecules can come from the area of RNA species and can be functional mRNA or miRNA, for example.
- Polypeptides can exist as simple linear polypeptides or as folded structural proteins. Molecules which act as toxins, growth-inhibiting substances, and also enzymes or molecules for inhibiting cell division come into consideration as proteins.
- RNA molecules are those which, for example, inhibit metabolic processes, impede cell division or promote malfunctions in the biological processes within the bacteria.
- a nucleic acid sequence is conceivable which encodes a nucleic acid molecule, a polypeptide and/or a fragment thereof which is at least 50% identical to the aforementioned antibacterial nucleic acid sequence or the antibacterial polypeptide.
- a nucleic acid sequence is preferably also conceivable which is at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, is at least 97%, at least 98%, at least 99% or 100% identical to the aforementioned antibacterial nucleic acid sequence or antibacterial polypeptide.
- the nucleic acid sequence is a naturally occurring nucleic acid sequence or a non-naturally occurring nucleic acid sequence which already occurs in bacteriophages or which has been introduced into the respective bacteriophages, for example by molecular biological methods. For example, these molecular biology methods may involve in vivo and/or in vitro recombination, gene transfer, CRISPR/Cas, Talen, or the like.
- the bacteriophage may belong to the order Caudovirales, Ligamenvirales or the like.
- the bacteriophage belongs to the family Ackermanviridae, Ampullaviridae, Bicaudaviridae, Clavaviridae, Corticoviridae, Fuselloviridae, Globuloviridae, Guttaviridae, Lipothrixviridae, Myoviridae, Plasmaviridae, Podoviridae, Portogloboviridae, Rudiviridae, Salterprovirus, Sphaerolipoviridae, Siphoviridae, Tristivrioma-dae, Tristivieridae, Tristivieridae, Tectivrioma-dae Inoviridae, Microviridae, Spiraviridae, Pleolipoviridae, Cystoviridae or Leviviridae.
- bacteriophages of at least one bacteriophage species are provided, preferably from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more bacteriophage species.
- the bacteriophages of a bacteriophage species specifically for at least one, and preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more intestinal and/or gastrointestinal bacterial species.
- the type of bacteria is known to the person skilled in the art and can easily be selected from databases, for example.
- the biological sample In the next step of the method according to the invention, it is necessary to bring the biological sample into contact with the bacteriophage and to incubate it.
- the "bringing into contact” can take place, for example, by dripping, injecting, laying on and/or another method known to the person skilled in the art for bringing bacteriophage into contact with the biological sample.
- incubation in connection with the method according to the invention relates to a method step in which the biological sample is incubated together with the bacteriophages for a certain period of time, with a proliferation cycle of the bacteriophages occurring, preferably under the appropriate conditions known to a person skilled in the art within the biological sample comprising the bacteria specific to the bacteriophages of at least one bacterial species.
- this method step also includes monitoring these until the population of the at least one bacterial species has been reduced by at least 70%.
- the implementation of the monitoring is sufficiently known to the person skilled in the art and can, for example, take place on the basis of a fixed period of time or also be based on the experience of the person skilled in the art, for example by observing the sample.
- a colored or otherwise optically visible indication can be provided which indicates that the population of the bacterial species has been reduced by at least 70%. This can be done, for example, by reaching the desired bacterial density or using a chemical and/or biochemical indicator, eg. by means of a coloring, a color change of the coloring or a loss of coloring.
- the steps of incubating and monitoring can take place alternately until the bacterial species has been reduced by at least 70%.
- the reduction in the population of the bacterial species is at least 70%.
- the reduction in the population can preferably also be more than 70%, for example at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 95.5%, at least 96%, at least 96.5%, at least 97%, at least 97.5%, at least 98%, at least 98.5%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99 .5%, at least 99.6%, at least 99.7%, at least 99.8%, at least 99.9%, at least 99.95%, at least 99.99% or 100%, with a reduction of at least 70% population of the bacterial species is considered significant and a reduction of at least 95% in the population of the bacterial species is considered significant.
- the person skilled in the art is aware that a reduction is 100% in the rarest of cases, but this can definitely be achieved when using suitable
- the person skilled in the art recognizes the success of the method, which justifies a sufficient antibacterial effect and thus a sufficient reduction in the intestinal and/or gastrointestinal bacterial species within the biological sample.
- the reduction in the population of the bacterial species can then be used as a measure of the effectiveness or success of a therapy based on the use of the corresponding bacteriophage.
- a reduction in a bacterial species can be aimed at, which is opposed to the life or lifestyle of a desired bacterial species that is beneficial to therapy. This means that the existence or growth of this type of bacteria can be achieved by reducing the type of bacteria that counteracts it but is specific to the bacteriophage. It will It is assumed here that an increase in a population of a desired bacterial species beneficial to therapy can result in the same effect on an organism as the reduction in a population of a bacterial species specific to the bacteriophage.
- the method according to the invention can therefore not only be carried out reliably and cost-effectively, but also quickly and easily, especially since the few method steps can be carried out in a standardized manner and a high success rate is achieved by a clear (more than 70% reduction) or significant (more than 95% reduction ) Reduction of bacterial species is achieved.
- the method can also be carried out using simple means and only devices known to the person skilled in the art are required for providing the biological sample and the bacteriophage, for bringing them into contact and for incubating them and for evaluating the reduction in the corresponding bacterial species within the population.
- step c) is followed by an evaluation of the reduction in the population of the intestinal and/or gastrointestinal bacterial species.
- evaluation ren is understandable to the person skilled in the art and relates to the analysis, evaluation and/or evaluation of step c). Since a reduction in the population of the bacterial species by at least 70% had already been monitored beforehand, this process step serves in particular to check the reduction achieved and optionally to record the result by making written records, photographs and film recordings, collecting and documenting data via counts , density measurements, growth determinations or similar methods and can be used for statistics with regard to the repeated implementation of the method according to the invention.
- the nucleic acid has two or more promoters and/or regulatory elements and/or that the nucleic acid encodes nucleic acid sequences for two or more nucleic acid molecules, polypeptides and/or fragments thereof.
- the nucleic acid preferably has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more promoters and/or regulatory elements on. More preferably, the nucleic acid encodes 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 nucleic acid molecules, and polypeptides /or fragments thereof.
- nucleic acid molecules, polypeptides and/or fragments thereof can have an antibacterial effect for one or more types of bacteria, it being preferred here that bacteriophages can infect several types of bacteria with such a nucleic acid.
- nucleic acid sequences are specific for killing a type of bacteria. It is essential that a special ders strong activation of the expression of the nucleic acid and thus a particularly increased and efficient production of the antibacterial nucleic acid, the antibacterial nucleic acid molecule, the antibacterial polypeptide and / or the fragment thereof can be achieved.
- a bacteriophage with such a nucleic acid can make a particularly efficient contribution to reducing the population of the bacterial species and, for example, significantly accelerate or significantly shorten step c) of the method according to the invention (the incubation). This leads to an increase in the efficiency of the method and to a reduction in the duration and/or costs when carrying out the method.
- the intestinal and/or gastrointestinal bacterial species is anaerobic and/or aerobic and the bacterial species is the Acidaminococcaceae, Actinobacteria, Actinomycineae, Alistipes, Bacteroides, Bacteroidetes, Bifidobacterium, Clostridium, Coprococcus, Coriobacterium , Desulfovibrio, Enterobacterium, Enterococcus, Escherichia, Erysipelotrichia, Firmicutes, Fusobacterium, Lactobacillus, Lachnospiracea, Paraprevotella, Porphyry omonadaceae, Prevotella, Propionibacterium, Proteobacteria, Rikenellacea, Ruminococcus, Streptococcus, Thermoanaerobacteria or Veillonella.
- an "aerobic” lifestyle means that the organism needs atmospheric oxygen to survive or is dependent on oxygen from the air.
- “anaerobic” describes a way of life that does not require oxygen, which means that the organism in question can maintain its molecular metabolism without oxygen.
- “obligate”, “tolerant” and “facultative” aerobic or anaerobic organisms it being understood by the person skilled in the art that "obligate” is used here means an exclusively aerobic or anaerobic way of life with the exclusion of the respective other oxygen situation.
- the term “facultative” means that, for example, anaerobic organisms basically operate a corresponding metabolism, but can switch to an aerobic metabolism in the presence of oxygen, and vice versa. Thus bacterial species can have an exclusively aerobic or anaerobic way of life or a combination of these.
- the mental, neurodegenerative and/or neurological disease and/or disorder is an affective disorder, such as mania, hypomania, depression, such as fatigue syndrome, chronic fatigue syndrome, reduced self-esteem and/or a perceived lower level of environmental recognition, a depressive disorder, such as recurrent depressive disorder, bipolar disorder, and/or a persistent mood disorder, such as cyclothymia and/or dysthymia, a personality disorder, such as multiple, paranoid, schizoid, dissocial, emotionally unstable, histrionic, anancastic (compulsive), anxious (avoidant), dependent (asthenic), and/or other personality disorder such as eccentric, baseless, narcissistic, passive-aggressive, psychoneurotic, and/or immature, a hallucination, a amnesia, a behavioral disorder a drug and/or drug abuse such as abuse, addiction, dependency, withdrawal syndrome and/or withdrawal symptoms, urtic disorder, a depressive disorder, such as recurrent de
- a social phobia a phobic disorder
- an anxiety disorder such as generalized anxiety disorder, agoraphobia, social phobia, acrophobia and/or a specific additional phobia
- a panic disorder an obsessive-compulsive disorder such as a compulsive act and/or obsession
- schizophrenia a schizotypal disorder, a schizoaffective disorder, a delusional disorder, a psychosis, a psychotic disorder, such as a transient or nonorganic psychotic disorder
- an eating disorder such as anorexia nervosa, bulimia, binge eating and/or pica syndrome
- a sleep disorder such as parasomnia, primary insomnia, somnambulism and/or pavo nocturnus
- a sexual dysfunction such as sexual desire disorder, hypersexuality, nymphomania, satyriasis and/or psychogenes such as vaginismus, anorgasmia, hyporgasmia, impotence
- a kit for carrying out the method according to the invention comprising a) a container comprising bacteriophages of at least one bacteriophage species which are specific for at least one intestinal and/or gastrointestinal bacterial species, the intestinal and/or gastrointestinal bacterial species being directly or indirectly a affects a mental, neurodegenerative and/or neurological disease and/or disorder of a host organism, and which comprise at least one nucleic acid functionally linked to a promoter and/or a regulatory element; and b) instructions for carrying out the method.
- kit refers to a collection of the aforementioned components (kit-of-parts), preferably provided separately or within a single container.
- the term "instructions for carrying out the method” refers to a numerical, written and/or graphic representation of the description, by means of which a simplification of the implementation of the method objective according to the invention is achieved. These can preferably be in the form of a manual or can be provided by a computer program, such as an application. Furthermore, it is conceivable that the computer program has an implemented algorithm that is able to carry out the determination, the comparison and/or the result thereof, which is referred to in the methods of the present invention.
- the computer program can be provided on a data storage medium or device such as an optical storage medium (e.g. compact disc) or directly on a computer or data processing device will.
- the instructions may preferably include standards for usage levels, as known to those skilled in the art.
- the instructions also include requirements for the storage and disposal of the container and the biological sample.
- the instructions for carrying out the method can contain tables, registers, databases or excerpts from the same about bacterial species and bacteriophage species known to the person skilled in the art, with information about the specificity and/or efficiency of the bacteriophage species also being given.
- a bacteriophage which comprises at least one nucleic acid functionally linked to a promoter and/or to a regulatory element, the bacteriophage being specific for at least one intestinal and/or gastrointestinal bacterial species, the intestinal and/or gastrointestinal bacterial species directly or indirectly affects a mental, neurodegenerative and/or neurological disease and/or disorder of a host organism and wherein the nucleic acid is selected from the group comprising: a) a nucleic acid sequence which codes for at least one antibacterial nucleic acid molecule; and b) a nucleic acid sequence encoding a nucleic acid molecule that is at least 50% identical to the nucleic acid molecule encoded by the nucleic acid sequences of a); and c) a nucleic acid sequence encoding at least one antibacterial polypeptide; and d) a nucleic acid sequence encoding a polypeptide that is at least 50% identical to a polypeptide encoded by the nucleic acid sequences of
- the bacteriophage according to the invention is described in detail elsewhere, the nucleic acid sequence being a naturally occurring nucleic acid sequence or a non-naturally occurring nucleic acid sequence which already occurs in the bacteriophage or which was introduced into the bacteriophage, for example by molecular biological methods.
- these molecular biology methods may involve in vivo and/or in vitro recombination, gene transfer, CRISPR/Cas, Talen, or the like, as known to those skilled in the art.
- the nucleic acid has two or more promoters and/or regulatory elements and/or that the nucleic acid encodes nucleic acid sequences for two or more nucleic acid molecules, polypeptides and/or fragments thereof. It is essential that a particularly strong activation of the expression of the nucleic acid and thus a particularly increased and efficient production of the antibacterial nucleic acid, the antibacterial nucleic acid molecule, the antibacterial polypeptide and/or the fragment thereof are achieved.
- the bacteriophage with such a nucleic acid can contribute particularly efficiently to the reduction of the population of the intestinal and/or gastrointestinal bacterial species or to the reduction of a bacterial species that opposes the way of life of this bacterial species. Furthermore, it is conceivable that the bacteriophage can infect several types of bacteria with such a nucleic acid.
- the intestinal and/or gastrointestinal bacterial species is anaerobic and/or aerobic.
- the assignment of the bacterial species is described in detail elsewhere.
- the mental, neurodegenerative and/or neurological disease and/or disorder according to the invention is described in detail elsewhere.
- bacteriophages and/or a pharmaceutical composition comprising bacteriophages and at least one other component as a drug to change the composition of the intestinal flora, as a drug to prevent the development and/or slow down the progression of the mental, neurodegenerative and/or neurological disease and/or or disorder and/or proposed as a drug in the treatment of the psychiatric, neurodegenerative and/or neurological disease and/or disorder, bacterial infection, metabolic disease, metabolic syndrome and/or cancer.
- the term "pharmaceutical composition” refers to a mixture of bacteriophage, which are fully defined elsewhere, and at least one other ingredient.
- further ingredients can be stabilizing agents, wetting agents, pharmaceutical carriers, pharmaceutically acceptable carriers, diluents, pharmaceutically acceptable diluents, additional pharmaceutically active ingredients, release agents and the like.
- Preferred diluents include water, alcohols, physiological saline, buffers such as phosphate buffered saline, syrup, oil, water, emulsions, various kinds of wetting agents, and the like.
- the carrier must be acceptable in the sense that it is compatible with the other components of the composition and not harmful to the host organism.
- the pharmaceutical carrier used can be a solid, gel or liquid.
- solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
- the carrier or diluent can be one well known in the art Contain time delay material such as glycerol monostearate or glycerol distearate alone or with a wax.
- Suitable carriers include those mentioned above and others known in the art such as Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, European Pharmacopoeia, US Homeopathic Pharmacopoeia, or HAB®.
- the pharmaceutically acceptable diluent is chosen so as not to adversely affect the biological activity of the combination.
- examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution and Hank's solution.
- the pharmaceutical composition may also contain other carriers, excipients or non-toxic, non-therapeutic, non-immunogenic stabilizers and the like.
- the bacteriophage and/or the pharmaceutical composition are to be adapted for the appropriate use. Accordingly, it is contemplated that the bacteriophage and/or pharmaceutical composition will be formulated for systemic or topical application, depending on the desired mode of administration. Preferably the bacteriophage and/or pharmaceutical composition is to be formulated for systemic or local application. Oral application, for example in the form of tablets, solutions and/or drinking ampoules, or topical application in gel form or application by injection, for example as an active or passive vaccine, is preferably provided. However, depending on the nature and mode of action, the bacteriophage and/or pharmaceutical composition may be administered by other routes, including dermal, intramuscular, subcutaneous, oral, rectal, retrograde, and/or intravenous administration. The precise, individually recommended dosage can, in principle, depend on other parameters that are well known to the person skilled in the art. For example, children may receive a different dosage than adults. If she The person skilled in the art can readily determine the dosage with the aid of various known calculation tools.
- the term "change in the composition of the intestinal flora" describes a process that can be understood by a person skilled in the art, in which at least one population of an intestinal and/or gastrointestinal bacterial species that is a component of the intestinal flora of the host organism is directly or indirectly affected by methods known to the person skilled in the art and increased, reduced, eliminated, inhibited and/or otherwise impaired as detailed elsewhere. Considered on its own, this can be measurable by determining the respective number of bacteria or can be determined in relation to other types of bacteria within the intestinal flora. Suitable methods for this are known to those skilled in the art.
- preventing the development of the mental, neurodegenerative and/or neurological disease and/or disorder is also understandable to a person skilled in the art and relates to the partial, complete, short-term, permanent and/or long-term avoidance of the onset of the disease and/or Disorder and/or its prevention/prophylaxis. It is preferably conceivable that this is achieved by reducing at least one type of intestinal and/or gastrointestinal bacteria.
- slowing down the progression of the mental, neurodegenerative and/or neurological disease and/or disorder is also understandable to a person skilled in the art and relates to the partial, complete, short-term, permanent and/or long-term maintenance of the condition achieved, as well as an improvement in the symptoms associated with the mental, neurodegenerative and/or neurological disease and/or disorder. It is preferably conceivable that this is achieved by reducing at least one type of intestinal and/or gastrointestinal bacteria.
- the use of the bacteriophages and/or the pharmaceutical composition as a medicament can be used in the treatment of mental, neurodegenerative and/or neurological diseases and/or disorders, diseases in the medical fields of oncology, immunology, infectology, dentistry, oral medicine and maxillofacial medicine , oto-rhino-laryngology, ophthalmology, neurology, gynaecology, gastroenterology, endocrinology, psychiatry, psychosomatics, orthopaedics, paediatrics, surgery, urology and/or the like.
- Possible diagnoses that may indicate the use of the bacteriophage and/or the pharmaceutical composition are, in addition to the mental, neurodegenerative and/or neurological disease and/or disorder mentioned, inter alia, the metabolic syndrome, type 2 diabetes mellitus, gallbladder diseases, chronic Diseases of the digestive tract, chronic intestinal inflammation, increased cholesterol levels, hyperacidity of the stomach, high blood pressure, lipid metabolism disorders, breathing difficulties, sleep apnea, coronary heart disease, arthrosis, gout, cancer diseases such as uterine, breast, cervical, pankeas, liver, stomach , lymph gland, skin, blood, colon, prostate and/or gallbladder cancer, sex hormone disorders, reduced libido, pain, increased risk of thrombosis and embolism and/or increased risk during operations and anesthesia.
- the metabolic syndrome type 2 diabetes mellitus, gallbladder diseases, chronic Diseases of the digestive tract, chronic intestinal inflammation, increased cholesterol levels, hyperacidity of the stomach, high blood pressure, lipid metabolism disorders,
- the aim in each case is preferably to reduce at least one intestinal and/or gastrointestinal bacterial species and thus to change the composition of the intestinal flora, as well as the development and/or progression of the mental, neurodegenerative and/or neurological disease and/or disorder as the main or to prevent and/or slow down side effects in order to obtain a good, preferably improved, prognosis for the treatment of the respective illness and/or respective suffering up to the point of healing the same.
- a use of the bacteriophages and/or the pharmaceutical composition is conceivable independently of the actual disease.
- a success will seen in the reduction of at least one intestinal and/or gastrointestinal bacterial species and/or the prevention of the development and/or slowing down of the progression of the mental, neurodegenerative and/or neurological disease and/or disorder.
- treatment refers to any improvement in the human and/or animal organism that occurs compared to an untreated human and/or animal organism, this improvement preferably being based on the reduction of at least one intestinal and/or gastrointestinal bacterial species Changing the composition of the intestinal flora and/or preventing the development and/or slowing down the progression of the mental, neurodegenerative and/or neurological disease and/or disorder of the human and/or animal organism. It is also conceivable that a cure of the same is possible. It is understood that one treatment may not be successful in all of the human and/or animal organisms to be treated. However, the term assumes that the treatment is successful for a statistically significant proportion of subjects (e.g. a cohort in a cohort study).
- Whether a part is statistically significant can be easily determined by a person skilled in the art using various known statistical evaluation tools, e.g. determination of confidence intervals, p-value determination, Student's t-test, Mann-Whitney test, etc.
- Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99%.
- the p-values are preferably 0.05, 0.01, 0.005 or 0.0001.
- drug refers to bacteriophage and/or a pharmaceutical composition in a therapeutically effective dose as detailed elsewhere.
- the pharmaceutical composition has bacteriophages, at least one pharmaceutically acceptable carrier and/or a diluent funds on.
- the drug may be formulated for various routes of administration, which are detailed elsewhere.
- a therapeutically effective dose refers to the amounts necessary to alter the composition of the gut flora, to reduce at least one intestinal and/or gastrointestinal bacterial species, to prevent the development and/or slow the progression and/or in the treatment of those mentioned elsewhere getting sick is necessary.
- the therapeutic effectiveness and toxicity can be determined by standard pharmaceutical methods in cell cultures or experimental animals, for example.
- ED50 the dose that is therapeutically effective at 50%
- LD50 the dose that is fatal at 50%
- the dose ratio between therapeutic and toxic effects is the therapeutic index, which can be expressed as the ratio LD50/ED50.
- the dosing regimen is determined by the treating physician and other clinical factors. As is well known in medicine, the appropriate dosage depends on many factors known to a person skilled in the art, including size, body surface area, age, the substance to be administered, sex, time and route of administration, general health and others at the same time administered medication. Progress can be monitored through periodic assessment.
- bacteriophages and/or a pharmaceutical composition comprising bacteriophages and at least one further component are proposed for use in the treatment of a metabolic disease, a cardiovascular disease, a bacterial infection, a metabolic disease, the metabolic syndrome and/or cancer .
- bacteriophages and/or a pharmaceutical composition comprising bacteriophages and at least one other component for use in a therapeutic Method or in a non-therapeutic method for changing the composition of the intestinal flora, in a therapeutic method or in a non-therapeutic method for preventing the development and/or slowing down the progression of the mental, neurodegenerative and/or neurological disease and/or disorder and /or proposed in a therapeutic method or in a non-therapeutic method for the treatment of a metabolic disease, a cardiovascular disease, a bacterial infection, a metabolic disease, the metabolic syndrome and/or cancer.
- the bacterial infection is a bacterial infection of the respiratory tract, teeth, mouth, jaw, eye, musculoskeletal system, blood, gastrointestinal tract, preferably a bacterial infection of the colon, small intestine, duodenum, stomach, liver, gallbladder and/or pancreas, skin, cardiovascular system, endocrine system, mind, immune system, nervous system, metabolism, wounds and/or urogenital tract.
- gastrointestinal tract can be understood by a person skilled in the art and relates to the organs of the human and/or animal organism which are used to absorb, break up, transport and/or process nutrients with the aim of making the nutrients available to the human and/or or animal's organism usable, the intestine, in particular through the intestinal flora, contributes significantly to the regulation of this.
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DE102020128879.4A DE102020128879A1 (de) | 2020-11-03 | 2020-11-03 | Verfahren zur Reduktion der Population mindestens einer intestinalen und/oder gastrointestinalen Bakterienart umfassend Bakteriophagen sowie Bakteriophagen und deren Verwendung |
PCT/EP2021/078868 WO2022096254A1 (de) | 2020-11-03 | 2021-10-19 | Verfahren zur reduktion der population mindestens einer intestinalen und/oder gastrointestinalen bakterienart umfassend bakteriophagen sowie bakteriophagen und deren verwendung |
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US (1) | US20230398162A1 (de) |
EP (1) | EP4240384A1 (de) |
JP (1) | JP2023547534A (de) |
KR (1) | KR20230110275A (de) |
CN (1) | CN116685339A (de) |
AU (1) | AU2021373228A1 (de) |
CA (1) | CA3189796A1 (de) |
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CA2940226A1 (en) * | 2013-02-22 | 2014-08-28 | The Regents Of The University Of California | Compositions and methods for promoting growth of beneficial microbes to treat or prevent disease or prolong life |
KR101381796B1 (ko) * | 2013-02-27 | 2014-04-25 | 씨제이제일제당 (주) | 신규 박테리오파지 및 이를 포함하는 항균 조성물 |
US20220348886A1 (en) * | 2018-01-19 | 2022-11-03 | Cytophage Technologies Inc. | Genetically Engineered Bacteriophage |
DE102020101859A1 (de) * | 2020-01-27 | 2021-07-29 | Oxana Karpf | Verfahren zur Reduktion der Population mindestens einer adipogenen Bakterienart umfassend Bakteriophagen sowie Bakteriophagen und deren Verwendung |
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- 2021-10-19 WO PCT/EP2021/078868 patent/WO2022096254A1/de active Application Filing
- 2021-10-19 US US18/034,746 patent/US20230398162A1/en active Pending
- 2021-10-19 AU AU2021373228A patent/AU2021373228A1/en active Pending
- 2021-10-19 EP EP21799202.3A patent/EP4240384A1/de active Pending
- 2021-10-19 CA CA3189796A patent/CA3189796A1/en active Pending
- 2021-10-19 JP JP2023527006A patent/JP2023547534A/ja active Pending
- 2021-10-19 KR KR1020237018389A patent/KR20230110275A/ko unknown
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JP2023547534A (ja) | 2023-11-10 |
KR20230110275A (ko) | 2023-07-21 |
US20230398162A1 (en) | 2023-12-14 |
CN116685339A (zh) | 2023-09-01 |
AU2021373228A1 (en) | 2023-06-15 |
WO2022096254A1 (de) | 2022-05-12 |
CA3189796A1 (en) | 2022-05-12 |
DE102020128879A1 (de) | 2022-05-05 |
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