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INHIBITORS OF PI3K-DELTA FOR TREATMENT OF SKIN INFLAMMATION

Award Number: R43AI092929
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/18/2011
PERIOD OF PERFORMANCE END DATE: 06/30/2013

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INHIBITORS OF PI3K-DELTA FOR TREATMENT OF SKIN INFLAMMATION - DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease that affects over a million people in the United States, disproportionately affecting women of childbearing age. The cutaneous variant of lupus (CLE) is 2-3 times more frequent then SLE itself and, although less severe, often leads to severe disability for work and poor quality of life. CLE is difficult to treat, and the few effective therapies have significant toxicities and side effects. Triggering of the innate receptors TLR7 and TLR9 by self nucleic acids in plasmacytoid dendritic cell (PDC) precursors and B cells is key in the pathogenesis of SLE, because this leads to the production of type I IFN and the production of anti-DNA and anti-RNP immune complexes, respectively. In CLE, as well, PDC massively infiltrate the lesional skin and produce type I IFNs, which play a major role in establishing a self- perpetuating inflammatory loop driving the disease. We have recently identified PI3K-delta (PI3K4) as a key signaling molecule of the TLR7&9 pathway for the production of IFN-1 by PDC, and have shown that this in-house synthesized small-molecule-based inhibitor is extremely efficient in both in vitro and in vivo assays. In addition, we have developed and fully characterized mouse models of skin inflammation in which IFN-1 production by infiltrating PDC in response to endogenous TLR7&9 ligands plays a major role in the development and progression of the disease. We have new preliminary data showing that the inhibitor of PI3K4 can reduce skin inflammation in our model. This proposal comprises several related activities to evaluate the PI3K4 inhibitor's effectiveness in cutaneous autoimmunity mediated by plasmacytoid dendritic cell activation and IFN-1 production. These studies include: " Dose and route-finding studies " Definition of the mechanism of action " Preclinical evaluation of PI3K4 in a mouse model of CLE The ultimate goal is the development of a topical formulation of an inhibitor of PI3K4 for the treatment of autoimmune skin diseases. Because of the ease in evaluating symptoms, diseases such as cutaneous lupus may prove to be particularly useful in the early phase of clinical development. PUBLIC HEALTH RELEVANCE: Cutaneous lupus is a serious autoimmune disease affecting over 1 million people in the U.S., primarily women. Current treatments for this disease have serious side effects; however, recent discoveries suggest new methods of treatment that may be safer and more effective. We propose to develop a novel drug that inhibits interferon-alpha production, a key factor in the disease, as a therapy for cutaneous lupus and related autoimmune diseases in the skin.


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: 2012 ( Subtotal = $292,359 )
2012	2012	DYNAVAX TECHNOLOGIES CORPORATION	2929 7th St Ste 100	Berkeley	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	2	6/22/2012	NON-COMPETING CONTINUATION	$292,359
														Subtotal = $292,359

Issue Date FY: 2011 ( Subtotal = $297,225 )
2011	2011	DYNAVAX TECHNOLOGIES CORPORATION	2929 7th St Ste 100	Berkeley	CA	94710	ALAMEDA	USA	Allergy and Infectious Diseases Research	000	1	7/18/2011	NEW	$297,225
														Subtotal = $297,225

Grand Total All Awards = $589,584

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INHIBITORS OF PI3K-DELTA FOR TREATMENT OF SKIN INFLAMMATION

Award Number: R43AI092929

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/18/2011

PERIOD OF PERFORMANCE END DATE: 06/30/2013

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