Gap junction-enhancing agents for treatment of necrotizing enterocolitis and inflammatory bowel disease

• US 10,172,848 B2
• Filed: 06/19/2013
• Issued: 01/08/2019
• Est. Priority Date: 12/22/2010
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Hackam, David J.
• Primary Examiner(s): Ha, Julie
• Assistant Examiner(s): Hellman, Kristina M
• Application Number:
  US13/921,865
• Publication Number:
  US 20130345154A1
• Time in Patent Office: 2,029 Days
• Field of Search: None
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The present invention relates to methods of reducing the risk of occurrence of, and/or treating, necrotizing enterocolitis (“NEC”) or inflammatory bowel disease (“IBD”) comprising administering, to a subject in need of such treatment, an effective amount of a gap junction enhancing agent (“GJEA”), for example a peptide (“GJP”) or peptide analog (“GJPA”). It is based, at least in part, on the discovery that greater functionality of gap junctions between enterocytes increases their rate of migration and reduces the severity of intestinal inflammation.

Claims

1. A method of treating necrotizing enterocolitis in a subject in need of such treatment comprising administering to the subject one or more dose of a gap junction enhancing agent, wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 10 mg/kg, and wherein the gap junction enhancing agent is selected from the group consisting of

(a) a peptide comprising a sequence selected from the group consisting of SEQ ID NO:

1-31; and

(b) a peptide analog selected from the group consisting of rotigaptide and GAP-134 ((2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid).

2. The method of claim 1 where the gap junction enhancing agent comprises a peptide having a sequence selected from the group consisting of SEQ ID NO:

1-31.

3. The method of claim 1 where the gap junction enhancing agent is rotigaptide.

10. The method of claim 1, wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 5 mg/kg.

11. The method of claim 10, wherein the one or more dose of the gap junction enhancing agent is between 0.1 mg/kg and 1 mg/kg.

4. A method of reducing the risk of occurrence of necrotizing enterocolitis in a subject in need of such treatment comprising administering to the subject one or more dose of a gap junction enhancing agent, wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 10 mg/kg, and wherein the gap junction enhancing agent is selected from the group consisting of

(a) a peptide comprising a sequence selected from the group consisting of SEQ ID NO:

1-31; and

(b) a peptide analog selected from the group consisting of rotigaptide and GAP-134 ((2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid).

5. The method of claim 4 where the gap junction enhancing agent comprises a peptide having a sequence selected from the group consisting of SEQ ID NO:

1-31.

6. The method of claim 4 where the gap junction enhancing agent is rotigaptide.

12. The method of claim 4, wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 5 mg/kg.

13. The method of claim 12, wherein the one or more dose of the gap junction enhancing agent is between 0.1 mg/kg and 1 mg/kg.

7. A method of inducing increased migration of enterocytes in a subject diagnosed with necrotizing enterocolitis, the method comprising administering to the subject one or more dose of a gap junction enhancing agent, wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 10 mg/kg, and wherein the gap junction enhancing agent is selected from the group consisting of

(a) a peptide comprising a sequence selected from the group consisting of SEQ ID NO:

1-31; and

(b) a peptide analog selected from the group consisting of rotigaptide and GAP-134 ((2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid).

8. The method of claim 7 where the gap junction enhancing agent comprises a peptide having a sequence selected from the group consisting of SEQ ID NO:

1-31.

9. The method of claim 7 where the gap junction enhancing agent is rotigaptide.

14. The method of claim 7, wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 5 mg/kg.

15. The method of claim 14, wherein the one or more dose of the gap junction enhancing agent is between 0.1 mg/kg and 1 mg/kg.