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SMALL MOLECULE INHIBITORS OF EFFECTOR TH-17 CELLS IN INFLAMMATORY BOWEL DISEASE

Award Number: R43DK079452
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2008
PERIOD OF PERFORMANCE END DATE: 06/30/2010

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SMALL MOLECULE INHIBITORS OF EFFECTOR TH-17 CELLS IN INFLAMMATORY BOWEL DISEASE - DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD), including Crohn's Disease and ulcerative colitis (UC), is a lifelong T cell- mediated inflammatory condition of the small intestine or colon. The highly proinflammatory cytokine interleukin-17 (IL-17) is elevated in proportion to disease activity in intestinal biopsies of both Crohn's and UC patients but is virtually absent in unaffected individuals. A new class of effector CD4+ T cells, known as Th-17 cells, has recently been identified that expresses IL-17 and several other inflammatory cytokines. The Th-17 cell is distinct from the better-studied Th1 and Th2 effector T cells and is the major T cell lineage implicated in animal models of colitis and other types of autoimmune disease. The applicants have identified structurally diverse small molecule antagonists to a previously unexplored orphan receptor that is required for CD4+ Th-17 cell differentiation. In cell culture, these receptor antagonists block Th-17 cell formation from na¿ve CD4+ T cells, inhibit the expansion of memory Th-17 cells following challenge by antigen, and suppress IL-17 release. These findings suggest that an orally bioavailable small molecule antagonist will have significant therapeutic potential in the treatment of IBD. This proposed new small molecule therapeutic class will also have significant therapeutic advantages--such as oral bioavailability and greater ease of administration--over injectable monoclonal antibodies to key cytokines in the Th-17 pathway such as IL-17 and IL-23. The specific aims of this proposal are to: (1) demonstrate that the novel receptor antagonists block IL-17 release in isolated intestinal tissue as expected if suppression of intestinal Th-17 is a target of the new compound class; (2) synthesize and characterize small molecule lead antagonists for in vivo studies from antagonists already identified at Orphagen; and (3) investigate lead antagonist suppression of disease activity in an established model of murine colitis that reflects Th-17 activity and is induced by transfer of na¿ve CD4+CD45RBhigh T cells to immunocompromised mice. Leads identified in this study will facilitate the identification of potential clinical candidates for treatment of IBD and other autoimmune indications in planned Phase II research. PUBLIC HEALTH RELEVANCE: Crohn's disease and ulcerative colitis are chronic, intestinal disorders for which treatment options are limited. The side effects of current medications are significant. We propose to characterize and develop a novel class of small molecule drugs that suppresses the formation and function of a novel lineage of T cells that appear to have a central role in the immune pathology of the disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2008	ORPHAGEN PHARMACEUTICALS	5310 EASTGATE MALL	SAN DIEGO	CA	92121	SAN DIEGO	USA	Digestive Diseases and Nutrition Research	000	1	1/30/2009	NEW	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $266,559 )
2008	2008	ORPHAGEN PHARMACEUTICALS	5310 EASTGATE MALL	SAN DIEGO	CA	92121	SAN DIEGO	USA	Digestive Diseases and Nutrition Research	000	1	6/19/2008	NEW	$266,559
														Subtotal = $266,559

Grand Total All Awards = $266,559

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SMALL MOLECULE INHIBITORS OF EFFECTOR TH-17 CELLS IN INFLAMMATORY BOWEL DISEASE

Award Number: R43DK079452

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2008

PERIOD OF PERFORMANCE END DATE: 06/30/2010

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