WO2022182329A1 - Phagothérapie de la dysbiose du microbiote intestinal, de la maladie du foie stéatosique non alcoolique et de la stéatohépatite non alcoolique - Google Patents

Phagothérapie de la dysbiose du microbiote intestinal, de la maladie du foie stéatosique non alcoolique et de la stéatohépatite non alcoolique Download PDF

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Publication number
WO2022182329A1
WO2022182329A1 PCT/US2021/019194 US2021019194W WO2022182329A1 WO 2022182329 A1 WO2022182329 A1 WO 2022182329A1 US 2021019194 W US2021019194 W US 2021019194W WO 2022182329 A1 WO2022182329 A1 WO 2022182329A1
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subject
bacterial species
composition
phage
kill
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PCT/US2021/019194
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English (en)
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Carl Merril
Greg Merril
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Adaptive Phage Therapeutics, Inc.
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Priority to PCT/US2021/019194 priority Critical patent/WO2022182329A1/fr
Publication of WO2022182329A1 publication Critical patent/WO2022182329A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2795/00—Bacteriophages
    • C12N2795/00011—Details
    • C12N2795/00032—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent

Definitions

  • the invention relates to the field of phage therapy, and is particularly directed at providing a phage-based method and composition for treating the gut microbiota (GM) of a subject in a manner wherein one or more bacterial species of the GM may be specifically targeted and killed.
  • the method and composition may be beneficial for treating a disease or condition associated with GM changes or gut dysbiosis such as NAFLD or NASH.
  • Non-alcoholic fatty liver disease is a very common disorder characterized by an excessive buildup of lipids (fat) in the liver (known as hepatic steatosis) due to causes other than the consumption of alcohol (Nonalcoholic Fatty Liver Disease & NASH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), November 2016). It has been estimated that in the United States alone, up to one quarter of the population may be affected (i.e. 75 to 100 million Americans (Rich N.E. et ah, Clin Gastroenterol Hepatol i6(2):i98-2io, 2018)), and while typically people with NAFLD are asymptomatic (i.e.
  • NASH non-alcoholic steatohepatitis
  • NAFLD neurotrophic factor
  • risk factors include overweight, conditions such as insulin resistance, obesity, diabetes, dyslipidemia and high blood pressure, as well as genetic predisposition (Younossi Z et ah, supra; Friedman SL et ah, Nat Med 24(7):9o8-922, 2018), and dietary or environmental factors, it is considered that there is a complex "interplay" between these factors causing alterations in lipid metabolism subsequently leading to excessive lipid accumulation in hepatocytes, culminating in the development of NAFLD (Kolodziejczyk A et al, EMBO Mol Med n:e9302, 2019).
  • GM gut microbiota
  • microbiome therapy intended to modulate the GM has been suggested.
  • NAFLD gut dysbiosis
  • GM dysbiosis gut dysbiosis
  • many of these treatments, which are intended to stimulate or supplement the GM have shown, in the limited studies undertaken to date, highly variable results, perhaps due to a lack of specificity in their effect and the diversified gut dysbiosis observed among NAFLD patients.
  • the present invention is directed at providing a method of treating the GM of a subject in a manner wherein one or more bacterial species of the GM (e.g. one or more bacterial species contributing to gut dysbiosis) may be specifically targeted and killed.
  • the method may be beneficial for treating a disease or condition associated with GM changes or gut dysbiosis such as NAFLD.
  • the method makes use of bacteriophages ("phages"), which are a diverse set of non-cellular infective agents that replicate within and can kill specific bacterial hosts.
  • the present invention relates to a method of treating the gut microbiota (GM) of a subject, comprising administering one or more phage type (e.g. one or more phage strains) to the subject to kill or inhibit growth of one or more bacterial species present in the subject's GM.
  • one or more phage type e.g. one or more phage strains
  • the method may enable specific "editing" of the GM by, for example, specifically killing one or more bacterial species present in an overly high or abnormal level(s), thereby altering or correcting any gut dysbiosis.
  • this may be beneficial for treating or attenuating the development of certain diseases or conditions including, for example, NAFLD and NASH.
  • the invention also relates to a therapeutic phage composition for treating the gut microbiota (GM) of a subject, comprising one or more phage type (e.g. one or more phage strains) which can kill or inhibit growth of one or more bacterial species present in the subject's GM.
  • a therapeutic phage composition for treating the gut microbiota (GM) of a subject, comprising one or more phage type (e.g. one or more phage strains) which can kill or inhibit growth of one or more bacterial species present in the subject's GM.
  • Such a composition may comprise one or more phage types (e.g. one or more phage type(s) including phage obtained from phage "stocks”) and, as such, the composition may comprise a phage "cocktail”.
  • phage types e.g. one or more phage type(s) including phage obtained from phage "stocks”
  • the composition may comprise a phage "cocktail”.
  • phage can be used to refer to a single phage or more than one phage.
  • the present invention can “comprise” (open ended) or “consist essentially of' the components of the present invention.
  • “comprising” means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited.
  • the terms “having” and “including” are also to be construed as open ended unless the context suggests otherwise.
  • the term “about” or “approximately” means within an acceptable range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system.
  • “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value.
  • the term can mean within an order of magnitude, preferably within 5 fold, and more preferably within 2 fold, of a value.
  • the term “about” means within an acceptable error range for the particular value, such as ⁇ 1-20%, preferably ⁇ 1-10% and more preferably ⁇ 1-5%. In even further embodiments, "about” should be understood to mean+/-5%.
  • the term "and/or" when used in a list of two or more items means that any one of the listed characteristics can be present, or any combination of two or more of the listed characteristics can be present.
  • the composition can contain A feature alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B, and C in combination.
  • bacteria refers to a non-cellular infective agent that reproduces only in a suitable host cell, that is, a bacterial host cell.
  • phage therapy refers to any therapy to treat a bacterial infection or a disease or condition that is caused by bacteria or which shows symptoms or disease/condition development or progress associated with the presence of bacteria, such as gut microbiota (GM) dysbiosis, and/or diseases or conditions which may otherwise be associated with GM dysbiosis (e.g. NAFLD or NASH).
  • Phage therapy may involve the administration to a subject requiring treatment (e.g. a patient) of one or more therapeutic phage composition that can be used to infect, kill or inhibit growth of a bacterium, which comprises one or more viable phage as an antibacterial agent (e.g. a composition comprising one phage type or a phage "cocktail").
  • a phage therapy may involve the administration of more than one therapeutic phage composition
  • the compositions may have a different host range (e.g. one may have a broad host range and one may have a narrow host range, and/ or one or more of the compositions may act synergistically with one another).
  • the therapeutic phage composition(s) used in a phage therapy will also typically comprise a range of inactive ingredients selected from a variety of conventional pharmaceutically acceptable excipients, carriers, buffers, and/or diluents.
  • pharmaceutically acceptable is used to refer to a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism.
  • pharmaceutically acceptable excipients examples include, but are not limited to, wetting or emulsifying agents, pH buffering substances, binders, stabilizers, preservatives, bulking agents, adsorbents, disinfectants, detergents, sugar alcohols, gelling or viscosity enhancing additives, flavoring agents, and colors.
  • Pharmaceutically acceptable carriers include macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, trehalose, lipid aggregates (such as oil droplets or liposomes), and inactive vims particles.
  • Pharmaceutically acceptable diluents include, but are not limited to, water and saline.
  • the present invention relates to a method of treating the gut microbiota (GM) of a subject, comprising administering one or more phage type (e.g. one or more phage strains) to the subject to kill or inhibit growth of one or more bacterial species present in the subject's GM.
  • one or more phage type e.g. one or more phage strains
  • the one or more phage type has been selected for their capacity to kill or inhibit growth of one or more bacterial species present in the GM in an overly high ("over-represented") or abnormal level(s).
  • the bacterial species may be non-pathogenic species commonly found in the GM of a subject, but which may be present in an overly high or abnormal level(s) when the subject is experiencing gut dysbiosis.
  • Whether or not a particular bacterial species present in the GM of a subject is present in an overly high or abnormal level can be readily determined by standard techniques well known to one of ordinary skill in the art including, for example, 16S rRNA sequence profiling of fecal (stool) samples or cecal fluid samples (i.e. as obtained via an intestinal tube) as previously described in, for example, Le Roy T et al, Gut 62:1787-1794, 2013 and Stanley D et al., BMC Microbiol 15:51-61, 2015).
  • the method of the invention may enable the alteration and correction of any gut dysbiosis.
  • the method of the invention may be beneficial for treating or attenuating the development of any disease or condition associated with gut dysbiosis.
  • the method of the invention may be performed on a subject with a disease or condition selected from, for example, metabolic diseases and conditions (e.g. overweight, obesity, insulin resistance and diabetes), Crohn's Disease, ulcerative colitis, inflammatory bowel disease (IBD), colon cancer, and asthma (Rajpal DK et al, supra).
  • the method of the invention maybe performed on a subject with a hepatic disease or condition such as, for example, NAFLD or NASH.
  • the one or more phage type administered to the subject may be selected for their capacity to kill or inhibit growth of one or more bacterial species, typically non-pathogenic bacterial species, present in the GM in an overly high or abnormal level(s).
  • the one or more phage type may be selected for their capacity to kill or inhibit growth of at least one bacterial species from the group consisting of Lachnospiraceae bacterium, B. intestinihominis, Lactobacillus, Staphylococcus, Proteobacteria, Enterobacteria, Escherichia, Bacteroides, Gammaproteobacteria and Prevotella.
  • the one or more phage type may be particularly selected for their capacity to kill or inhibit growth of at least one bacterial species selected from those that have been reported to be overly high in the GM of individuals within this patient group or, otherwise, in relevant animal models, including Lachnospiraceae bacterium, Barnesiella intestinihominis (Le Roy T et al, supra), Lactobacillus gasseri, Lactobacillus taiwanensis (Zeng H et al, J Nutr 143:627-631, 2013), Proteobacteria, Enterobacteria, Escherichia (Zhu L et al, Hepatology 57:601-609, 2013), Bacteroides (Boursier J et al, Hepatology 63:764-775, 2016), Gammaproteobacteria and Prevotella (Michail S et al,
  • the one or more phage type may be selected from stocks of phage, which maybe held in storage in an inventory or "phage bank". Selection maybe performed, for example, through the use of empirical laboratory techniques that have been developed to screen for phage susceptibility on bacterial strains, such as by in vitro screening phage for their capacity to lyse (kill) or inhibit bacterial growth by testing individual phage types against a specific subject's bacterial isolate(s) from the gut using either liquid cultures or bacterial lawns grown on agar media.
  • Bacterial isolates for screening may be readily obtained from fecal samples or cecal fluid samples taken from a subject according to standard techniques. For example, a small amount of a fecal sample (e.g.
  • 0.1 g may be diluted into a suitable medium (e.g. 9qqm1 of a standard culture broth) and aliquots (e.g. ioom ⁇ ) plated out onto suitable agar plates for incubation. Following incubation, colonies may be carefully collected using routine techniques including scraping of the plate surface with a cell scraper and thereafter storing the collected samples (for later use) or culturing to expand the cell population. Aliquots of the collected samples may optionally be used to extract bacterial nucleic acid to enable identification of the bacterial species present in the fecal sample through, for example, amplification and sequencing of 16S rRNA genes by well known standard techniques (e.g.
  • the one or more phage type administered to the subject has been selected by screening of phage for their capacity to lyse or inhibit growth of one or more bacterial species previously obtained from the subject's GM.
  • Such embodiments maybe regarded as a personalized medicine approach.
  • the one or more phage type administered to the subject has been selected by screening of phage for their capacity to lyse or inhibit growth of one or more bacterial species previously obtained from the GM of at least one other subject such as another subject with the same or similar disease or condition to the subject being treated (e.g. where the method of the invention maybe performed on a subject with NAFLD, then one or more phage will have been selected by screening for their capacity to lyse or inhibit growth of one or more bacterial species previously obtained from at least one other subject with NAFLD).
  • the one or more phage have been selected by screening for their capacity to lyse or inhibit growth of one or more bacterial species previously obtained from two or more other subjects with the same or similar disease or condition to the subject being treated, then such embodiments maybe regarded as an epidemiologically matched approach.
  • the one or more phage type may be administered to the subject by any suitable route of administration.
  • preferred routes of administration include oral and intravenous (i.u.) routes (e.g. i.v. infusion).
  • the one or more phage type may be administered to the subject in the form of the therapeutic phage composition.
  • the phage included in such a composition will comprise phage obtained from phage stocks.
  • the composition will comprise a phage cocktail.
  • the one or more phage type may be administered to the subject in an effective amount; that is, an amount that is sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • an effective amount is sufficient for treating a disease or condition or otherwise to palliate, ameliorate, stabilize, reverse, slow or delay the progression of a disease or condition such as, for example, the development of NASH in a subject with NAFLD.
  • the one or more phage type may be administered to the subject as a combination therapy involving the administration of a further active agent or preparation such as, for example: (i) one or more antibiotics, one or more bactericides, and/or one or more other therapeutic molecules such as a small molecule or biologic that has bactericidal activity; or (ii) one or more agents such as a small molecule or preparation intended to supplement or promote the growth one or more bacterial species present in the subject's GM such as, for example, a pre-, pro- or syn-biotic preparation.
  • a further active agent or preparation such as, for example: (i) one or more antibiotics, one or more bactericides, and/or one or more other therapeutic molecules such as a small molecule or biologic that has bactericidal activity; or (ii) one or more agents such as a small molecule or preparation intended to supplement or promote the growth one or more bacterial species present in the subject's GM such as, for example, a pre-, pro- or syn-biotic
  • the one or more phage type is used in combination with the administration of a pre-, pro- or syn-biotic preparation for supplementing or promoting the growth of Bacteriodes vulgatus, Firmicutes, Clostridium and/or Lactobacillus (e.g. a probiotic preparation comprising viable B. vulgatus, Firmicutes spp., Clostridium spp. and/or Lactobacillus spp. including L. rhamnosus, L. plantarum, L. gasseri, L. johnsonii and L.
  • a probiotic preparation comprising viable B. vulgatus, Firmicutes spp., Clostridium spp. and/or Lactobacillus spp. including L. rhamnosus, L. plantarum, L. gasseri, L. johnsonii and L.
  • the one or more phage will be selected such that they do not kill or inhibit growth of the bacterial species that is to be supplemented or whose growth is intended to be promoted.
  • the one or more phage type can be administered in a single composition (i.e. a therapeutic phage composition comprising the further active agent or preparation) or in separate compositions. If administered in separate compositions, the therapeutic phage composition and the further active agent or preparation may be administered simultaneously or sequentially in any order (e.g. within seconds or minutes (e.g. 5 to 60 mins) or even hours (e.g. 2 to 48 hours)).
  • the method of the invention will typically be performed on a human subject. However, as will be readily apparent to one of ordinary skill in the art, the method may also be useful in veterinary contexts.
  • the subject maybe an animal subject such as, for example, a livestock animal, companion animal such as a dog or cat, or exotic animal such as a lion or elephant.
  • the invention also relates to a therapeutic phage composition for treating the gut microbiota (GM) of a subject, comprising one or more phage type (e.g. one or more phage strains) which can kill or inhibit growth of one or more bacterial species present in the subject's GM.
  • a therapeutic phage composition for treating the gut microbiota (GM) of a subject, comprising one or more phage type (e.g. one or more phage strains) which can kill or inhibit growth of one or more bacterial species present in the subject's GM.
  • the one or more phage type has been selected for the capacity to kill or inhibit growth of one or more bacterial species (which may be non- pathogenic species commonly found in the GM of a subject) present in the GM in an overly high or abnormal level(s).
  • the one or more phage type may have been selected for the capacity to kill or inhibit growth of at least one bacterial species from the group consisting of Lachnospiraceae bacterium, B. intestinihominis, Lactobacillus, Staphylococcus, Proteobacteria, Enterobacteria, Escherichia, Bacteroides, Gammaproteobacteria and Prevotella.
  • the therapeutic phage composition may be beneficial for treating or attenuating the development of any disease or condition associated with gut dysbiosis.
  • the therapeutic phage composition may be used to treat a subject with a disease or condition selected from, for example, a hepatic disease or condition such as NAFLD or NASH, other metabolic diseases and conditions, Crohn's Disease, ulcerative colitis, IBD, colon cancer, and asthma.
  • the therapeutic phage composition may be formulated for administration to the subject by any suitable route of administration, but preferably, by oral or intravenous (i.u.) routes (e.g. i.v. infusion).
  • i.u. oral or intravenous routes
  • i.v. infusion e.g. i.v. infusion
  • the therapeutic phage composition may also be formulated to include a further active agent or preparation such as: (i) one or more antibiotics, one or more bactericides, and/ or one or more other therapeutic molecules such as a small molecule or biologic that has bactericidal activity; or (ii) one or more agents such as a small molecule or preparation intended to supplement or promote the growth one or more bacterial species present in the subject's GM such as, for example, a pre-, pro- or syn- biotic preparation.
  • a further active agent or preparation such as: (i) one or more antibiotics, one or more bactericides, and/ or one or more other therapeutic molecules such as a small molecule or biologic that has bactericidal activity; or (ii) one or more agents such as a small molecule or preparation intended to supplement or promote the growth one or more bacterial species present in the subject's GM such as, for example, a pre-, pro- or syn- biotic preparation.
  • the composition comprises one or more phage type selected for the capacity to kill or inhibit growth of at least one bacterial species from the group consisting of Lachnospiraceae bacterium, Barnesiella intestinihominis, Lactobacillus, Staphylococcus, Proteobacteria, Enterobacteria, Escherichia, Bacteroides, Gammaproteobacteria and Prevotella, and a pre-, pro- or syn-biotic preparation for supplementing or promoting growth of Bacteriodes vulgatus, Firmicutes, Clostridium and/ or Lactobacillus (e.g.
  • a probiotic preparation comprising viable B. vulgatus, Firmicutes spp., Clostridium spp. and/or Lactobacillus spp. including L. rhamnosus, L. plantarum, L. gasseri, L.johnsonii and L. reuteri).
  • the therapeutic phage composition may be formulated so as to provide a suitable dose of each phage type included in the composition.
  • a suitable dose of the phage(s) may be in the range of lo ⁇ to io 1 ⁇ ’. pfu, and more preferably 109 to 10 12 pfu.
  • the therapeutic phage composition is formulated to provide a dose of each phage type present of about 10 11 pfu.
  • liver function tests shows that his condition had worsened considerably, with results showing a substantial increase in the ALT level (105 U/L), an increase in aspartate aminotransferase (AST) such that the AST: ALT ratio is > 0.8, and also an increase in the level of alkaline phosphatase (ALP).
  • ALT level 105 U/L
  • AST aspartate aminotransferase
  • ALP alkaline phosphatase
  • GM gut microbiota
  • Fecal samples are collected from the patient and sent to a pathology laboratory for isolation of bacterial DNA and sequence analysis of the V1-V3 region of the 16S rRNA gene using a suitable 16S rRNA sequence database.
  • this testing indicates that the patient has a very significant over-representation of B. intestinihominis within his GM.
  • the recommendation is made to use phage therapy to address the patient's GM dysbiosis.
  • Samples of the B. intestinihominis are isolated from the fecal samples obtained and screened for phage susceptibility using a proprietary phage bank using either liquid cultures or bacterial lawn grown on agar media. Subsequently, a phage is selected for the phage therapy, propagated overnight in a liquid culture of B. intestinihominis and then formulated for oral administration in a suitable liquid carrier (1 mL) to provide a dose of the phage of 10 11 pfu.

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Abstract

L'invention concerne le domaine de la phagothérapie et concerne particulièrement la fourniture d'un procédé et d'une composition à base de phages pour traiter le microbiote intestinal d'un patient de sorte qu'une ou plusieurs espèces bactériennes du microbiote intestinal peuvent être spécifiquement ciblées et tuées. Le procédé et la composition peuvent être utiles pour traiter une maladie ou un état associé à des changements de microbiote intestinal ou une dysbiose intestinale telle que la NAFLD (de l'anglais « non-alcoholic faftty liver disease » pour « maladie du foie stéatosique non alcoolique ») ou la SHNA (stéatose hépatique non alcoolique).
PCT/US2021/019194 2021-02-23 2021-02-23 Phagothérapie de la dysbiose du microbiote intestinal, de la maladie du foie stéatosique non alcoolique et de la stéatohépatite non alcoolique WO2022182329A1 (fr)

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