Reversing intestinal inflammation by inhibiting retinoic acid metabolism

• US 9,623,013 B2
• Filed: 12/08/2015
• Issued: 04/18/2017
• Est. Priority Date: 08/23/2011
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Bhattacharya, Nupur, Penny, Hweixian Leong, Engleman, Edgar George
• Primary Examiner(s): RAO, SAVITHA M
• Application Number:
  US14/962,782
• Publication Number:
  US 20160158206A1
• Time in Patent Office: 497 Days
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031

Abstract

An agent that increases local concentration of retinoic acid (RA) in the intestine through modifying enzymatic pathways involved in RA metabolism is administered in a dose effective to inhibit or reverse production of inflammatory mediators by intestinal dendritic cells and thereby reduce intestinal inflammation and tumor growth associated with intestinal inflammation.

Claims

1. A method of treating an individual who has (i) one or more adenomas in the intestine, colon, and/or rectum, and (ii) a mutation in the adenomatous polyposis coli (APC) gene, the method comprising:

administering to the individual an effective dose of an agent to reverse and/or prevent disease progression in said individual, wherein the agent increases local concentration of retinoic acid (RA).

2. The method of claim 1, wherein the agent is not RA.

3. The method of claim 2, wherein the agent increases local concentration of retinoic acid (RA) through modifying enzymatic pathways involved in RA metabolism.

4. The method of claim 3, wherein the agent increases activity of retinaldehyde dehydrogenase or retinol dehydrogenase in intestinal tissues.

5. The method of claim 4, wherein the agent inhibits activity of a retinoic acid catabolizing enzyme.

6. The method of claim 5, wherein the retinoic acid catabolizing enzyme is a protein of the CYP26 family.

7. The method of claim 6, wherein the retinoic acid catabolizing enzyme is CYP26A1.

8. The method of claim 7, wherein the agent comprises one or more of:

liarozole, talarozole, ketoconazole, [S—

(R*,R*)]-N-[4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]2-benzothiazolamine (R116010), and (R)—

N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (R115866).

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

10. The method of claim 1, wherein the individual has familial adenomatous polyposis (FAP).

11. A method of reducing chronic intestinal inflammation in an individual with a mutation in the adenomatous polyposis coli (APC) gene, the method comprising:

administering to the individual an effective dose of an agent to reduce intestinal inflammation, wherein the agent increases local concentration of retinoic acid (RA).

12. The method of claim 11, wherein the agent is not RA.

13. The method of claim 12, wherein the agent increases local concentration of retinoic acid (RA) through modifying enzymatic pathways involved in RA metabolism.

14. The method of claim 13, wherein the agent increases activity of retinaldehyde dehydrogenase or retinol dehydrogenase in intestinal tissues.

15. The method of claim 14, wherein the agent inhibits activity of a retinoic acid catabolizing enzyme.

16. The method of claim 15, wherein the retinoic acid catabolizing enzyme is a protein of the CYP26 family.

17. The method of claim 16, wherein the retinoic acid catabolizing enzyme is CYP26A1.

18. The method of claim 17, wherein the agent comprises one or more of:

liarozole, talarozole, ketoconazole, [S—

(R*,R*)]-N-[4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]2-benzothiazolamine (R116010), and (R)—

N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (R115866).

19. The method of claim 18, wherein the agent is Liarozole or Talarozole.

20. The method of claim 11, wherein said administering comprises oral administration.

21. The method of claim 11, wherein the individual has familial adenomatous polyposis (FAP).