The Development of TLR Antagonists for Therapy of Hepatic Fibrosis and Cirrhosis

DESCRIPTION (provided by applicant): Hepatic fibrosis (HF) is a major health problem leading to cirrhosis and death. There is currently no pharmacological treatment for HF, and liver transplantation is unable to meet the needs of all patients afflicted with HF. We have shown that chronic liver injury involves the activation of Toll-like receptor 7 (TLR7) and TLR9. We further demonstrated that the TLR7/9 oligonucleotide-based antagonist IRS954, developed by Dynavax, blocks the development of HF when given prophylactically. This project attempts to confirm and expand the preclinical feasibility data and potential for IRS954 to be a novel therapy for HF with the following Specific Aims: Aim 1: Evaluate the pharmacokinetics and tissue distribution of IRS954 innormal and HF animals by clinically relevant dosing routes of administration. a. Compare levels of IRS954 in the liver of normal animals dosed intraperitoneally with those of animals receiving more clinically relevant subcutaneous and intravenous dosing.b. Compare the levels of IRS954 in the liver of normal and HF mice with the optimal dosing conditions from part a. Aim 2: Establish the activity of IRS954 in blocking progression and in promoting regression of HF. a. Test the ability of IRS954 to inhibitearly and late fibrotic phases using dosing conditions determined from Aim 1. b. Test the ability of IRS954 to promote fibrotic regression. Results from the above aims will provide additional supporting, preclinical evidence of the feasibility and utility of IRS954 as a potential therapeutic to limit progression and reverse HF. PUBLIC HEALTH RELEVANCE Public Health Relevance: The goal of this project is to improve the management of fibrotic liver disease by developing novel anti-fibrotic therapies thatdisrupt multiple pathological processes through targeting the TLR7 and TLR9 pathway. PUBLIC HEALTH RELEVANCE: When the liver is repeatedly injured by alcohol abuse or hepatitis viral infection, hepatic fibrosis is part of the response to these injuries, and if left untreated it can lead to irreversible liver damage (cirrhosis) and further serious complications such as hypertension, liver failure, and liver cancer. Currently, liver transplantation is the only definitive therapy for cirrhosis and it is not available to most patients. This project will determne whether a novel molecule has the potential to be a therapeutic to stop the progression or reverse hepatic fibrosis following liver injury.