Reversing intestinal inflammation by inhibiting retinoic acid metabolism

• US 10,039,751 B2
• Filed: 03/20/2017
• Issued: 08/07/2018
• 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: Penny, Hweixian Leong, Engleman, Edgar George, Bhattacharya, Nupur
• Primary Examiner(s): Rao, Savitha M
• Application Number:
  US15/464,010
• Publication Number:
  US 20170189384A1
• Time in Patent Office: 505 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 reducing polyp development and/or tumor burden in an individual who has a mutation in the adenomatous polyposis coli (APC) gene, the method comprising:

administering to the individual an effective dose of an agent to reduce polyp development and/or tumor burden 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 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 8, wherein the agent is Liarozole or Talarozole.

10. The method of claim 1, wherein the agent is Liarozole or Talarozole.

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

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

13. The method of claim 3, wherein said administering comprises oral administration.

14. The method of claim 3, wherein the individual has familial adenomatous polyposis (FAP).

15. The method of claim 6, wherein said administering comprises oral administration.

16. The method of claim 6, wherein the individual has familial adenomatous polyposis (FAP).

17. The method of claim 8, wherein said administering comprises oral administration.

18. The method of claim 8, wherein the individual has familial adenomatous polyposis (FAP).

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

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