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Screening for Inhibitors of TLR8 for Treatment of Rheumatoid Arthritis

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43AI100376-01A1
Agency Tracking Number: R43AI100376
Amount: $404,918.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NIAID
Solicitation Number: PA10-123
Timeline
Solicitation Year: 2012
Award Year: 2012
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
2929 7TH ST, STE 100
BERKELEY, CA -
United States
DUNS: 964173801
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 ROBERT COFFMAN
 (510) 665-7224
 rcoffman@dynavax.com
Business Contact
 ROBERT COFFMAN
Phone: (510) 665-7224
Email: rcoffman@dynavax.com
Research Institution
 Stub
Abstract

DESCRIPTION (provided by applicant): Autoimmune diseases develop when the adaptive immune response targets self-antigens, leading to inflammation and tissue destruction. The innate immune system faces the same fundamental challenge as the adaptive immune system - distinguishing self from non-self antigens - and there is now considerable evidence that recognition of self nucleic acids through toll-like receptors (TLRs) can contribute significantly t sterile inflammation and autoimmunity, with the clearest example being the role played by TLR9 and TLR7 in the pathogenesis of systemic lupus erythematosus (SLE). One of the innate receptors for RNA, TLR8, is a potent stimulator of inflammatory cytokines such as IL6 and TNF- , and its expression by multiple cell types involved in inflammatory diseases suggests likely involvement in autoimmunity. However, the lack of useful animal models, a consequence of the very different ligand specificity of human TLR8 and its rodent orthologs, has proven to be a major limitation in the study of TLR8 function. We have developed new tools that we hope will help better understand the biology of TLR8 and that have provided important new evidence for a role of TLR8 signaling in rheumatoid arthritis. The key objective of this proposalis to develop small-molecule antagonists of human TLR8 that can be tested for efficacy, first in the novel animal models we have developed, and ultimately in patients. The principal activities will include: Establishment of a cell-based screening strategy for huTLR8 antagonists. Screening multiple libraries of well-characterized compounds. Confirmation of the specificity of hits from these screening activities. If successful, this project will demonstrate the feasibility of developng a small-moleculeinhibitor for human TLR8, and will provide the lead compounds that can be rigorously tested for potential use in the treatment of rheumatoid arthritis. PUBLIC HEALTH RELEVANCE: Many drugs targeting pro-inflammatory cytokines have proven clinically beneficial; however, the mechanisms and triggering signals underlying the production of these cytokines in various autoimmune diseases are still poorly understood. We have found that a key receptor of innate immune responses, human Toll-Like Receptor- 8,can mediate multiple forms of autoimmunity, most notably rheumatoid arthritis, when triggered in mice. We propose to screen compound libraries for small molecules that inhibit this receptor and the subsequent pro- inflammatory response as a therapy for rheumatoid arthritis.

* Information listed above is at the time of submission. *

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