Compositions and Methods

• US 20140328803A1
• Filed: 06/24/2014
• Published: 11/06/2014
• Est. Priority Date: 02/04/2013
• Status: Active Grant

• Current Assignee: Seres Therapeutics, Inc.
• Original Assignee: Seres Health Inc.
• Inventors: Cook, David N., von Maltzahn, Geoffrey, Aunins, John Grant, Henn, Matthew R., Berry, David Arthur, McKenzie, Gregory, McKenzie, Mary-Jane Lombardo, Vulic, Marin, Goodman, Brian, Winkler, Jonathan
• Granted Patent: US 9,180,147 B2
• Time in Patent Office: Days
• US Class Current: 424/93.3
• 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, comprising administering to a human subject a composition comprising a purified population of spore-forming bacteria consisting essentially of a population of germinatable bacterial spores in an amount effective to populate 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, thereby providing an amount effective to treat 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 administration of the composition modulates the microbiota diversity present in the gastrointestinal tract of the subject.

3. 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.

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

5. The method of claim 4, wherein the purified population is substantially depleted of a detectable level of a first pathogenic material.

6. The method of claim 1, wherein the purified population is derived from a fecal material and is substantially depleted of a residual habitat product of the fecal material.

7. The method of claim 6, 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.

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

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores comprise at least two bacterial entities comprising 16S rRNA sequences at least 97% identical to the nucleic acid sequences selected from the group consisting of SEQ ID NO. 1670, SEQ ID NO. 674, SEQ ID NO. 1664, SEQ ID NO. 381, SEQ ID NO. 774, SEQ ID NO. 773, SEQ ID NO. 1051, SEQ ID NO. 673, SEQ ID NO. 848, SEQ ID NO. 875, SEQ ID NO. 847, SEQ ID NO. 856, SEQ ID NO. 1639, SEQ ID NO. 1045, SEQ ID NO. 1638, SEQ ID NO. 880, SEQ ID NO. 1896, SEQ ID NO. 1004, SEQ ID NO. 133, SEQ ID NO. 132, SEQ ID NO. 164, SEQ ID NO. 606, SEQ ID NO. 845, SEQ ID NO. 841, SEQ ID NO. 1386, and SEQ ID NO. 599.

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

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores comprise at least two bacterial entities selected from the group consisting of SEQ ID NO. 1670, SEQ ID NO. 674, SEQ ID NO. 1664, SEQ ID NO. 381, SEQ ID NO. 774, SEQ ID NO. 773, SEQ ID NO. 673, SEQ ID NO. 848, SEQ ID NO. 847, SEQ ID NO. 856, SEQ ID NO. 1639, SEQ ID NO. 1638, SEQ ID NO. 880, SEQ ID NO. 1896, SEQ ID NO. 1004, SEQ ID NO. 133, SEQ ID NO. 132, SEQ ID NO. 841, and SEQ ID NO. 599.

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

11. 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).

12. A method of treating or preventing a dysbiosis associated with a gastrointestinal disease in a subject, comprising administering a composition comprising a purified population of spore-forming bacteria consisting essentially of a population of germinatable bacterial spores produced by the steps of:

a) providing a fecal material, and

b) subjecting the fecal material to a treatment step resulting in purification of germinatable bacterial spores,

wherein an effective amount of the purified population administered to a subject treats a dysbiosis, prevents the dysbiosis, or reduces a severity of at least one symptom of the dysbiosis in the subject.

13. The method of claim 12, wherein administration 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.

14. The method of claim 12, wherein the dysbiosis is associated with 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.

15. The method of claim 12, wherein the composition comprises at least 1×

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores comprise at least two bacterial entities comprising 16S rRNA sequences at least 97% identical to the nucleic acid sequences selected from the group consisting of SEQ ID NO. 1670, SEQ ID NO. 674, SEQ ID NO. 1664, SEQ ID NO. 381, SEQ ID NO. 774, SEQ ID NO. 773, SEQ ID NO. 1051, SEQ ID NO. 673, SEQ ID NO. 848, SEQ ID NO. 875, SEQ ID NO. 847, SEQ ID NO. 856, SEQ ID NO. 1639, SEQ ID NO. 1045, SEQ ID NO. 1638, SEQ ID NO. 880, SEQ ID NO. 1896, SEQ ID NO. 1004, SEQ ID NO. 133, SEQ ID NO. 132, SEQ ID NO. 164, SEQ ID NO. 606, SEQ ID NO. 845, SEQ ID NO. 841, SEQ ID NO. 1386, and SEQ ID NO. 599.

16. The method of claim 12, wherein the composition comprises at least 1×

10⁴ colony forming units of germinatable bacterial spores per dose of the composition, and wherein the germinatable bacterial spores comprise at least two bacterial entities selected from the group consisting of SEQ ID NO. 1670, SEQ ID NO. 674, SEQ ID NO. 1664, SEQ ID NO. 381, SEQ ID NO. 774, SEQ ID NO. 773, SEQ ID NO. 673, SEQ ID NO. 848, SEQ ID NO. 847, SEQ ID NO. 856, SEQ ID NO. 1639, SEQ ID NO. 1638, SEQ ID NO. 880, SEQ ID NO. 1896, SEQ ID NO. 1004, SEQ ID NO. 133, SEQ ID NO. 132, SEQ ID NO. 841, and SEQ ID NO. 599.

17. The method of claim 12, 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 after the composition is administered;

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.

18. A method of preventing the onset a dysbiosis, comprising administering to a human subject a composition comprising a purified population of spore-forming bacteria consisting essentially of a population of germinatable bacterial spores in an amount effective to populate 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, thereby providing an amount effective to prevent the onset of the dysbiosis in the gastrointestinal tract in the human subject.

19. The method of claim 18, wherein the human subject has received one or more doses of an antibiotic therapy.

20. The method of claim 18, wherein the composition is administered as a complement to an antibiotic therapy.