Research Project
10216498
Summary Alcoholic Steatohepatitis (ASH) and Nonalcoholic Steatohepatitis (NASH) affects a large population in US and worldwide. Currently, major unmet medical needs include lack of method or agent to specifically deplete activated HSC and capillarized LSEC as well as noninvasive methodology and reagents to visualize collagen build-up, HSC activation, and LSEC capillarization in fibrotic liver. We have developed a protein drug candidate (referred to as ?ProAgio?) that targets integrin ?v?3 at a novel site to induce apoptosis of integrin ?v?3 expressing cells by a novel mechanism. ProAgio specifically induces apoptosis of integrin ?v?3 expressing cells with a high efficacy by recruiting & activating caspase 8 at cytoplasmic domain of???. We demonstrated in our preliminary studies that treatment of mice that carries liver fibrosis/cirrhosis induced by TAA/alcohol CCl4 and the high-fat diet induce NASH mice with ProAgio reversed liver fibrosis/cirrhosis. In addition, we have developed novel protein MRI contrast agents (ProCAs) that allow us to assess collagen contents and integrin ?v?3 positive HSCs & LSECs in fibrotic liver. MR imaging of fibrotic mice demonstrated superior properties of our developed contrast agents for collagen and integrin ?v?3 positive cell assessment. Preliminary toxicity analyses with healthy mice indicate that ProAgio and our developed MRI contrast agents are not toxic to mice at very high dose. The goal of this project is to vigorously pre-clinical validation of ProAgio as a drug candidate for ASH/NASH patient treatment. We will achieve our objective by three specific aims. Aim 1 is to examine the effectiveness of ProAgio in reversal of liver fibrosis using high-fat diet plus multiple binge alcohol and chronic alcohol binge induced ASH models. Investigation of the effects of ProAgio in ASH mouse models will further pre-clinical validation of ProAgio as an ASH/NASH treatment drug. Aim 2 is to monitor and validate the effects of ProAgio on collagen and ?HSC in fibrotic liver by MR imaging using our developed MRI contrast agents. Our MR imaging aided validation will not only validate the effectiveness of ProAgio as an ASH/NASH treatment agent, but also validate the target and mechanism of drug action. Aim 3 is Pre-clinical validations of ProAgio as an ASH/NASH treatment drug candidate via toxicology (TOX) and pharmacokinetic (PK) analyses. Our study will open a new avenue for ASH/NASH treatment and diagnosis/prognosis by protein design. Success in our studies will not only develop a new protein drug for liver fibrosis/cirrhosis treatment but also test highly effective MRI contrast agents that allow us to accurately and non-invasively monitor fibrosis progression and regression for assessment of treatment effects. Such development is expected to fill in the major medical gaps and to facilitate to devise treatment strategy to reverse fibrosis and follow high risk patients.
