TLR Signal Inhibition: a Novel Therapeutic Paradigm

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) are a family of 11 known cell surface receptors described on immune cells, which initiate proinflammatory signaling pathways in response to pathogen-associated molecular components or environmentally-induced cell damage. Several lines of evidence suggest that overexpression of TLRs and TLR signaling on nonimmune cells, specifically TLRS and 4, is the basis for the induction of a broadly prevalent array of autoimmune, inflammatory diseases (e.g. Type 1 diabetes, colitis, autoimmune thyroiditis, atherosclerosis). Pathologic TLR signaling has recently been identified as a target for the next generation of therapeutics. Our company has identified a class of compounds, tautomeric cyclic thiones (TCT), that we believe can inhibit pathologic TLR expression and/or signaling and fit this need. The long term goal is to develop TCTs as a therapeutic platform useful in treating autoimmune/inflammation. To begin to meet this goal, we will pursue the following aims with Phase 1 STTR funding. Specific Aim 1: To determine the mechanism by which C10 blocks pathologic TLRS and TLR4 expression/signaling in nonimmune human tissues. We have identified a lead TCT (C10) that (i) blocks pathologically induced TLRS expression/signaling in a nonimmune rat cell line, (ii) exhibits significant efficacy in murine models of autoimmune/inflammatory disease in which TLRs have been implicated and (iii) has no toxic side effects in animal models thus far examined. To significantly advance the development of C10, we will achieve the following critical milestones: (i) determine if C10 can inhibit pathological induction of TLRS and TLR4 signaling/expression in human nonimmune tissues and (ii) determine the mechanism of action of C10 on the TLR pathway in human nonimmune cells. Specific Aim 2: To develop an oral formulation of C10 that is stable and efficacious in vivo. Since we have several clinical indications for C10, we are in a position to move forward to preclinical toxicology studies as a prelude to Phase I/II clinical trials in humans. Preclinical toxicity studies must be done in a final formulation. Thus, we seek to establish a final oral formulation for C10 that can be used in preclinical toxicology studies. Using in vitro cell models and animal models of toxic shock and inflammatory bowel disease, we will develop an optimal oral formulation and dose of C10 that is stable and exhibits significant efficacy in these models. Lay description: We have identified a class of compounds that exhibit significant efficacy in mouse models of human autoimmune/inflammatory diseases. We seek to advance the development of these compounds which may eventually be used to treat a wide array of human pathologies.