Compositions and methods

• US 9,011,834 B1
• Filed: 03/04/2014
• Issued: 04/21/2015
• Est. Priority Date: 02/04/2013
• Status: Active Grant

• Current Assignee: Seres Therapeutics, Inc.
• Original Assignee: Seres Health Inc.
• Inventors: McKenzie, Gregory, McKenzie, Mary-Jane Lombardo, 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 MARK
• Application Number:
  US14/197,044
• Publication Number:
  US 20150093360A1
• Time in Patent Office: 413 Days
• Field of Search: None
• US Class Current: 424/93.1
• 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 inhibiting a dysbiosis, comprising administering an effective amount of a composition consisting of a population of germinatable bacterial spores and a pharmaceutically acceptable excipient to a subject, wherein the effective amount of the composition administered to the subject populates the gastrointestinal tract in the subject and augments growth of at least one type of bacteria not detectably present in the composition or in the gastrointestinal tract prior to administration, thereby treating the dysbiosis, inhibiting the dysbiosis, or reducing a severity of at least one symptom of the dysbiosis in the subject.

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

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

10. The method of claim 1, wherein the population of germinatable bacterial spores is substantially free of a first pathogenic material or the first pathogenic material is inactive.

11. The method of claim 10, wherein the population of germinatable bacterial spores is substantially free of a detectable level of a first pathogenic material.

12. The method of claim 1, wherein the population of germinatable bacterial spores is derived from a fecal material and is substantially free of a residual habitat product of the fecal material.

13. The method of claim 12, wherein the fecal material is obtained from a healthy subject not having a detectable level of a pathogen or a pathobiont prior to production of the fecal material.

14. The method of claim 1, wherein the composition consists of at least 1×

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores consists of at least two bacterial entities comprising 16S rDNA sequences at least 97% identical to the nucleic acid sequences selected from the group consisting of SEQ ID NO. 381, SEQ ID NO. 572, SEQ ID NO. 601, SEQ ID NO. 652, SEQ ID NO. 659, SEQ ID NO. 673, SEQ ID NO. 674, SEQ ID NO. 774, SEQ ID NO. 839, SEQ ID NO. 845, SEQ ID NO. 847, SEQ ID NO. 848, SEQ ID NO. 856, SEQ ID NO. 874, SEQ ID NO. 880, SEQ ID NO. 886, SEQ ID NO. 1049, SEQ ID NO. 1591, SEQ ID NO. 1655, SEQ ID NO. 1657, SEQ ID NO. 1670, and SEQ ID NO. 1896.

15. The method of claim 1, wherein the composition consists of at least 1×

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores consists of at least two bacterial entities comprising 16S rDNA sequences at least 97% identical to the nucleic acid sequences selected from the group consisting of SEQ ID NO. 374, SEQ ID NO. 381, SEQ ID NO. 543, SEQ ID NO. 556, SEQ ID NO. 572, SEQ ID NO. 601, SEQ ID NO. 646, SEQ ID NO. 673, SEQ ID NO. 674, SEQ ID NO. 774, SEQ ID NO. 843, SEQ ID NO. 847, SEQ ID NO. 848, SEQ ID NO. 856, SEQ ID NO. 880, SEQ ID NO. 1045, SEQ ID NO. 1049, SEQ ID NO. 1056, SEQ ID NO. 1415, and SEQ ID NO. 1896.

16. The method of claim 8, wherein the composition consists of at least 1×

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores consists of at least two bacterial entities comprising 16S rDNA sequences at least 97% identical to the nucleic acid sequences selected from the group consisting of SEQ ID NO. 381, SEQ ID NO. 572, SEQ ID NO. 601, SEQ ID NO. 652, SEQ ID NO. 659, SEQ ID NO. 673, SEQ ID NO. 674, SEQ ID NO. 774, SEQ ID NO. 839, SEQ ID NO. 845, SEQ ID NO. 847, SEQ ID NO. 848, SEQ ID NO. 856, SEQ ID NO. 874, SEQ ID NO. 880, SEQ ID NO. 886, SEQ ID NO. 1049, SEQ ID NO. 1591, SEQ ID NO. 1655, SEQ ID NO. 1657, SEQ ID NO. 1670, and SEQ ID NO. 1896.

17. The method of claim 9, wherein the composition consists of at least 1×

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores consists of at least two bacterial entities comprising 16S rDNA sequences at least 97% identical to the nucleic acid sequences selected from the group consisting of SEQ ID NO. 381, SEQ ID NO. 572, SEQ ID NO. 601, SEQ ID NO. 652, SEQ ID NO. 659, SEQ ID NO. 673, SEQ ID NO. 674, SEQ ID NO. 774, SEQ ID NO. 839, SEQ ID NO. 845, SEQ ID NO. 847, SEQ ID NO. 848, SEQ ID NO. 856, SEQ ID NO. 874, SEQ ID NO. 880, SEQ ID NO. 886, SEQ ID NO. 1049, SEQ ID NO. 1591, SEQ ID NO. 1655, SEQ ID NO. 1657, SEQ ID NO. 1670, and SEQ ID NO. 1896.

18. The method of claim 8, wherein the composition consists of at least 1×

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores consists of at least two bacterial entities comprising 16S rDNA sequences at least 97% identical to the nucleic acid sequences selected from the group consisting of SEQ ID NO. 374, SEQ ID NO. 381, SEQ ID NO. 543, SEQ ID NO. 556, SEQ ID NO. 572, SEQ ID NO. 601, SEQ ID NO. 646, SEQ ID NO. 673, SEQ ID NO. 674, SEQ ID NO. 774, SEQ ID NO. 843, SEQ ID NO. 847, SEQ ID NO. 848, SEQ ID NO. 856, SEQ ID NO. 880, SEQ ID NO. 1045, SEQ ID NO. 1049, SEQ ID NO. 1056, SEQ ID NO. 1415, and SEQ ID NO. 1896.

19. The method of claim 9, wherein the composition consists of at least 1×

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores consists of at least two bacterial entities comprising 16S rDNA sequences at least 97% identical to the nucleic acid sequences selected from the group consisting of SEQ ID NO. 374, SEQ ID NO. 381, SEQ ID NO. 543, SEQ ID NO. 556, SEQ ID NO. 572, SEQ ID NO. 601, SEQ ID NO. 646, SEQ ID NO. 673, SEQ ID NO. 674, SEQ ID NO. 774, SEQ ID NO. 843, SEQ ID NO. 847, SEQ ID NO. 848, SEQ ID NO. 856, SEQ ID NO. 880, SEQ ID NO. 1045, SEQ ID NO. 1049, SEQ ID NO. 1056, SEQ ID NO. 1415, and SEQ ID NO. 1896.

21. The method of claim 11, wherein the detectable level is detected by qPCR.

22. The method of claim 13, wherein the detectable level is detected by qPCR.

23. The method of claim 12, wherein the residual habitat product is a virus, fungus, or mycoplasma.

24. The method of claim 1, wherein the type of bacteria is a species.

2. A method of treating or inhibiting a dysbiosis in a subject, comprising administering a composition consisting of a population of germinatable bacterial spores and a pharmaceutically acceptable excipient, wherein the population of germinatable bacterial spores is produced by a) providing a fecal material and b) subjecting the fecal material to a treatment resulting in purification of germinatable bacterial spores in an amount effective to treat the dysbiosis, inhibit the dysbiosis, or reduce a severity of at least one symptom of the dysbiosis in the subject.

20. The method of claim 2, wherein the dysbiosis is a gastrointestinal disease, disorder or condition selected from the group consisting of Clostridium difficile-induced diarrhea, irritable bowel syndrome (IBS), colonization with a pathogen or pathobiont, infection with a drug-resistant pathogen or pathobiont, colitis, and Crohn'"'"'s Disease.

3. A method of treating or preventing a dysbiosis in a subject, comprising:

obtaining a fecal material;

treating the fecal material to obtain a purified population of spore-forming bacteria;

generating from the purified population a composition of spore-forming bacteria consisting of a population of germinatable bacterial spores; and

administering the composition to a subject in an amount effective to treat the dysbiosis, prevent the dysbiosis, or reduce the severity of at least one symptom of the dysbiosis in the subject.

4. The method of claim 3, wherein at least one type of spore-forming bacteria in the composition is not detectably present in the gastrointestinal tract of the subject prior to administration of the composition to the subject.

5. The method of claim 3, wherein administering the composition results in augmenting growth of at least one type of bacteria not detectably present in the composition or in the gastrointestinal tract prior to administration.

6. The method of claim 3, wherein administering the composition results in at least two of:

i) reduction or 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; and

iii) augmentation of at least one type of spore-forming or non-spore forming bacteria in the gastrointestinal tract of the subject that is not present in the composition.

7. The method of claim 3, wherein administering the composition results in a reduction or an elimination of at least one pathogen and/or pathobiont present in the gastrointestinal tract and at least one of:

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

ii) augmentation in the gastrointestinal tract of the subject of at least one type of bacteria not present in the therapeutic composition.

25. The method of claim 4, wherein the type of bacteria is a species.

26. The method of claim 5, wherein the type of bacteria is a species.

27. The method of claim 6, wherein the type of bacteria is a species.

28. The method of claim 7, wherein the type of bacteria is a species.