Sunday, May 5, 2024
5/5/2024
PROJECT SUMMARY/ABSTRACT The overall goal of this revised proposal is to address the important unmet need for noninvasive detection and assessment of liver fibrogenesis, the pathologic process resulting in liver scarring and fibrosis. Fibrosis is the cumulative end-result of all chronic liver diseases (CLD) that affect ~1.5 billion people globally. This study will be enabled by using positron emission tomography (PET) through specific in-vivo targeting of the activated (fibrogenic) hepatic stellate cells (HSCs), the cornerstone of liver fibrogenesis and fibrosis. While non-invasive techniques for assessment of fibrosis have been developed and validated (e.g., magnetic resonance elastography, MRE), there is lack of a much-needed non-invasive biomarker to measure fibrogenesis, which is especially significant in the setting of drug-discovery. Development trials and eventual clinical im- plementation of antifibrotic drugs require non-invasive detection and quantification of active fibrogenesis. As a current limitation, assessment of treatment response through measuring fibrosis requires several months due to the time lag between reduction in fibrogenesis and subsequent decrease in fibrosis. Moreover, even if a drug is effective, MRE may not detect a change in liver stiffness despite improvement in histologic, serologic, and/or other imaging markers. Hence, non-invasive assessment of liver fibrogenesis is urgently needed. We have demonstrated successful non-invasive preclinical assessment of liver fibrogenesis through a fundamentally innovative strategy using PET. Fibroblast activation protein (FAP) is specifically expressed by activated HSCs. We have demonstrated that in our human-sized model of alcohol-induced liver injury, uptake of radiolabeled FAP inhibitor (FAPI) on PET directly correlates with fibrogenesis and fibrosis. Moreover, mouse studies have demonstrated reduced FAP expression with fibrosis reversal. However, there is need for sys- tematic evaluation of the relationship between FAPI PET and tissue markers of fibrogenesis (1) across all grades of liver injury, and (2) in both presence and absence of the hepatotoxin. This requires further preclinical evaluation of FAPI PET in a controlled setting and subsequent translational evaluation in patients. We aim to (1) Determine the relationship between liver FAPI uptake and tissue markers of fibrogenesis across all stages of liver injury in our swine model of liver injury; (2) demonstrate that decreasing liver FAPI uptake is a biomarker for decrease in fibrogenesis and its tissue markers, preceding any reversal in fibrosis; (3) determine the rela- tionship between liver FAPI uptake and tissue markers of fibrogenesis in a pilot clinical study in CLD patients. Successful completion of these aims by our unique and highly qualified multidisciplinary team will lay the foundation for future clinical trials for definitive validation in patients and to fulfill the unmet need of a non- invasive biomarker for liver fibrogenesis. The development of this biomarker will have a meaningful impact on the care of ~1.5 billion people with CLD through (1) facilitating the development of antifibrotic pharmacothera- peutics (2) early detection of fibrogenic liver disease, and (3) monitoring of fibrogenesis in response to treatment.
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