Compositions and methods

• US 9,446,080 B2
• Filed: 03/11/2016
• Issued: 09/20/2016
• Est. Priority Date: 02/04/2013
• Status: Active Grant

• Current Assignee: Seres Therapeutics, Inc.
• Original Assignee: Seres Therapeutics, Inc.
• Inventors: Lombardo McKenzie, Mary-Jane, McKenzie, Gregory, Cook, David N., Vulic, Marin, von Maltzahn, Geoffrey, Goodman, Brian, Aunins, John Grant, Henn, Matthew R., Berry, David Arthur, Winkler, Jonathan
• Primary Examiner(s): Navarro, Albert
• Assistant Examiner(s): NAVARRO, ALBERT MARK
• Application Number:
  US15/068,438
• Publication Number:
  US 20160184370A1
• Time in Patent Office: 193 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 35/37 Digestive system
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 35/741 Probiotics probiotic yeast, e.g. saccharomyces A61K36/06
• CPC Class Codes: A61K 35/742 Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
• CPC Class Codes: A61K 35/744 Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
• CPC Class Codes: A61K 35/745 Bifidobacteria
• CPC Class Codes: A61K 35/747 Lactobacilli, e.g. L. acidophilus or L. brevis
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C12N 1/20 Bacteria; Culture media therefor
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are therapeutic compositions containing non-pathogenic, germination-competent bacterial spores, for the prevention, control, and treatment of gastrointestinal diseases, disorders and conditions and for general nutritional health.

Claims

1. A method of treating or reducing a severity of at least one symptom of a gastrointestinal disease associated with a dysbiosis, the method comprising

administering to a human subject a composition consisting essentially of a purified population of germinable bacterial spores in an amount effective to populate at least one region of a gastrointestinal tract in the subject and augment growth of at least one type of bacteria not detectably present in the composition or in the gastrointestinal tract prior to administration to the subject,

wherein the composition comprises at least 1×

10⁴ colony forming units of germinable bacterial spores per dose of the composition,

and the germinable bacterial spores comprise at least two different bacterial entities, each bacterial entity comprising a 16S rDNA at least 97% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NO. 673, SEQ ID NO. 674, SEQ ID NO. 774, SEQ ID NO. 845, SEQ ID NO. 847, SEQ ID NO. 848, SEQ ID NO. 856, and SEQ ID NO. 1670,

thereby treating the gastrointestinal disease or reduce a severity of at least one symptom of the gastrointestinal disease in the subject.

2. The method of claim 1, wherein populating the gastrointestinal tract by the germinable bacterial spores is determined by 16S profiling, qPCR, or colony counting.

3. The method of claim 1, wherein the at least one region of the gastrointestinal tract is selected from the group consisting of the stomach, the small intestine, the large intestine, and the rectum.

4. The method of claim 1, wherein the at least one type of bacteria not detectably present in the composition or in the gastrointestinal tract of the subject prior to treatment is selected from the group consisting of Bacteroides sp. 2_1_22, Streptococcus anginosus, Prevotella intermedia, Prevotella nigrescens, Oribacterium sp. ACB7, Prevotella salivae, Bacteroides intestinalis, Bifidobacterium dentium, Alcaligenes faecalis, Rothia dentocariosa, Peptoniphilus lacrimalis, Anaerococcus sp. gpac155, Sutterella stercoricanis, Bacteroides sp. 3_1_19, Parabacteroides goldsteinii, Bacteroides dorei, Bacteroides massiliensis, Lactobacillus iners, Granulicatella adiacens, Eggerthella sp. 1_3_56FAA, Gordonibacter pamelaeae, Finegoldia magna, Actinomyces nasicola, Streptobacillus moniliformis, Oscillospira guilliermondii, Orientia tsutsugamushi, Christensenella minuta, Clostridium oroticum, Clostridium sp. D5,Clostridium glycyrrhizinilyticum, Coprococcus comes, Ruminococcus lactaris, Ruminococcus torques, Clostridiales sp. SS3/4, Clostridium hylemonae, Clostridium aerotolerans, Clostridium asparagiforme, Clostridium sp. M62/1, Clostridium symbiosum, Lachnospiraceae genomosp. Cl. Blautia sp. M25, Blautia stercoris, Ruminococcus hansenii, Ruminococcus obeum, Ruminococcus sp. 5_1_39BFAA, Bryantella formatexigens, Eubacterium cellulosolvens, Clostridium sp. HGF2, Clostridium bartlettii, Clostridium bifermentans, Clostridium glycolicum, Eubacterium tenue, Dorea formicigenerans, Dorea longicatena, Lachnospiraceae bacterium 2_1_46FAA, Lachnospiraceae bacterium 9_1_43BFAA, Ruminococcus gnavus, Clostridium hathewayi, Blautia hydrogenotrophica, Clostridiaceae bacterium END-2, Roseburia faecis, Roseburia hominis, Roseburia intestinalis, Eubacterium sp. WAL 14571, Erysipelotrichaceae bacterium 5_2_54FAA, Eubacterium biforme, Eubacterium dolichum, Coprococcus catus, Acetivibrio ethanolgignens, Anaerosporobacter mobilis, Bacteroides pectinophilus, Eubacterium hallii, Eubacterium xylanophilum, Anaerostipes caccae, Clostridiales bacterium 1_7_47FAA, Clostridium aldenense, Clostridium citroniae, Eubacterium hadrum, Acetanaerobacterium elongatum, Faecalibacterium prausnitzii, Gemmiger formicilis, Eubacterium ramulus, Lachnospiraceae bacterium 3_1_57FAA CT1, Lachnospiraceae bacterium A4, Lachnospiraceae bacterium DJF VP30, Holdemania filiformis, Clostridium orbiscindens, Pseudoflavonifractor capillosus, Ruminococcaceae bacterium D16, Acetivibrio cellulolyticus, Eubacterium limosum, Anaerotruncus colihominis, Clostridium methylpentosum, Clostridium sp. YIT 12070, Hydrogenoanaerobacterium saccharovorans, Eubacterium ventriosum, Eubacterium eligens, Lachnospira pectinoschiza, Lactobacillus rogosae, Clostridium leptum, Eubacterium coprostanoligenes, Ruminococcus bromii, Clostridium viride, Butyrivibrio crossotus, Coprococcus eutactus, Eubacterium ruminantium, Eubacterium rectale, Roseburia inulinivorans, Butyricicoccus pullicaecorum, Eubacterium desmolans, Papillibacter cinnamivorans, Sporobacter termitidis, and Clostridium lactatifermentans.

5. The method of claim 1, wherein the dose is provided in a capsule.

6. The method of claim 5, wherein the capsule is a hypromellose capsule.

7. The method of claim 6, wherein the capsule is overencapsulated with a second capsule.

8. The method of claim 1, wherein the dose is provided in more than one capsule.

9. The method of claim 8, wherein the capsule is a hypromellose capsule.

10. The method of claim 9, wherein the capsule is overencapsulated with a second capsule.

11. The method of claim 1, each bacterial entity comprising a 16S rDNA selected from the group consisting of SEQ ID NO. 673, SEQ ID NO. 674, SEQ ID NO. 774, SEQ ID NO. 845, SEQ ID NO. 847, SEQ ID NO. 848, SEQ ID NO. 856, and SEQ ID NO. 1670.

12. The method of claim 1, each bacterial entity comprising a 16S rDNA at least 97% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs:

673, 674, 774, 848, and 1670.

13. The method of claim 1, wherein each bacterial entity comprises a 16S rDNA selected from the group consisting of SEQ ID NOs:

673, 674, 774, 848, and 1670.

14. The method of claim 1, wherein administration of the composition modulates the microbiota diversity present in the gastrointestinal tract of the subject.

15. The method of claim 1, wherein the gastrointestinal disease, disorder or condition is selected from the group consisting of Clostridium difficile-induced diarrhea, irritable bowel syndrome (IBS), infection or colonization with a pathogen or pathobiont including a drug resistant pathogen or pathobiont, colitis, a metabolic disorder, and Crohn'"'"'s disease.

16. The method of claim 1, wherein the gastrointestinal disease, disorder or condition is Clostridium difficile-induced diarrhea.

17. The method of claim 1, wherein a pathogenic material in the purified population is depleted or inactive.

18. The method of claim 17, wherein the purified population is substantially depleted of a detectable level of a first pathogenic material.

19. The method of claim 18, wherein the detectable level is detected by qPCR.

20. The method of claim 1, wherein the purified population of germinable spores is derived from a fecal material after reduction of a residual habitat product of the fecal material.

21. The method of claim 20, wherein the residual habitat product is a virus, fungus, or mycoplasma.

22. The method of claim 20, wherein the fecal material is obtained from a validated mammalian donor subject not having a detectable level of a pathogen or a pathobiont prior to production of the fecal material.

23. The method of claim 22, wherein the detectable level is detected by qPCR.

24. The method of claim 1, wherein administering comprises oral administration.

25. The method of claim 1, wherein administering the composition results in i) a reduction or an elimination of at least one pathogen and/or pathobiont present in the gastrointestinal tract of the subject;

ii) engraftment in the gastrointestinal tract of the subject of at least one type of spore-forming bacteria present in the composition;

or iii) a combination of i) and ii).

26. The method of claim 1, wherein the human subject has received one or more doses of an antibiotic therapy.

27. The method of claim 1, wherein the composition is administered as a complement to an antibiotic therapy.

28. The method of claim 1, wherein

administration of the composition modulates the microbiota diversity present in the gastrointestinal tract of the subject;

the gastrointestinal disease, disorder or condition is Clostridium difficile-induced diarrhea;

administering comprises oral administration; and

administering the composition results in i) a reduction or an elimination of at least one pathogen and/or pathobiont present in the gastrointestinal tract of the subject;

ii) engraftment in the gastrointestinal tract of the subject of at least one type of spore-forming bacteria present in the composition;

or iii) a combination of i) and ii).

29. The method of claim 28, each entity comprising a 16S rDNA at least 97% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs:

673, 674, 774, 848, and 1670.

30. The method of claim 28, wherein the dose is provided in more than one hypromellose capsule each overencapsulated with a second capsule.