Abstract Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide[1-4]. Hepatic fibrosis can develop in patients with any type of chronic liver disease (CLD), including alcoholic liver disease (ALD), hepatitis C, hepatitis B, nonalcoholic fatty liver disease (NAFLD) and autoimmune hepatitis. The major clinical consequences of cirrhosis are liver failure and hepatocellular carcinoma (HCC), both of which increase the risk of death. Alcoholic liver disease (ALD) is a leading cause of liver disease and liver-related deaths globally, particularly in developed nations. The current gold standard diagnostic method, liver biopsy is invasive and has many limitations including sampling error and high inter-observer variability even for the diagnosis of advanced stages of liver fibrosis. None of several technologies investigated as alternatives offers the desired sensitivity and specificity for the early detection and staging of fibrosis. Thus, an innovative, safe MRI contrast agent is required to overcome several major limitations including low sensitivity and specificity for early stage fibrosis and detection in heterogeneous tissue. Our team has pioneered a new class of gadolinium based contrast agents which utilize a protein scaffold to bind Gd3+ atoms. We have shown that ProCA32.collagen, a collagen 1 targeted protein MRI contrast agent, exhibits strong affinity to collagen I, whose expression level and spatial pattern depend on the stage of fibrosis. ProCA32.collagen possesses high relaxivities per particle (r1 and r2) at both 1.4 and 7.0 T, which enables the robust detection of early-stage alcohol-induced liver fibrosis and nonalcoholic steatohepatitis in animal models via dual contrast modes. Our preliminary studies on toxicity profiles and in vivo stability of our compound in animals using non-GLP grade materials have provided confidence that the compound will exhibit good sensitivity and specificity for early detection of liver fibrosis in human clinical trials. In Phase I of this proposal, we seek timely support for conducting IND enabled CMC studies for generating GLP/cGMP grade ProCA32.collagen. In Phase II, we will conduct toxicity and safety profile studies using GLP/cGMP grade products to complete IND required studies for clinical trials.

Narratives The novel contrast agent combined with innovative processing techniques made possible by this agent promise to markedly enhance the precision of MRI in diagnosing and monitoring liver fibrosis, filling in the major medical gap for quantitative staging of disease progression and monitoring the responses to therapy by non-invasive MRI.