Preventing liver fibrosis in alcoholic hepatitis by enhancing liver regenerative capacity via transient telomere extension using lipid nanoparticle-encapsulated TERT mRNA

Abstract Rejuvenation Technologies Inc. (RTI) aims to prevent liver fibrosis in alcoholic hepatitis (AH) by enhancing liver regenerative capacity. AH is an acute form of alcoholic liver disease with mortality of up to 50% within 1 month of presentation. Most AH patients exhibit advanced fibrosis/cirrhosis, which contributes to acute-on-chronic liver failure. RTI will ameliorate/prevent this fibrosis by implementing a method for the therapeutic extension of telomeres, the DNA sequences that protect chromosome ends. Telomeres naturally shorten over time and with cell division, eventually exposing the DNA end and triggering a DNA damage response that induces cell senescence and death. Accelerated telomere attrition has been identified as a plausible driver of fibrosis in AH and other fibrotic liver diseases. Thus, to combat AH-related fibrosis, RTI will use lipid nanoparticles (LNPs) to encapsulate nucleoside-modified mRNA (modRNA) encoding the telomerase reverse transcriptase (TERT) protein to transiently extend telomeres in proliferating hepatocytes. Animal studies have demonstrated the potential of this approach, as telomere extension reduces hepatocyte loss and fibrosis in a mouse model of liver cirrhosis. Moreover, RTIandapos;s preliminary results have shown that a single intravenous dose of TERT LNPs in mice extends liver telomeres by an average of 230 bp, reversing the equivalent of 5 years of telomere shortening in humans. Notably, TERT LNPs only increase telomerase activity for about 24 hours, after which the extended telomeres resume shortening at their normal rate, leaving the important anti-cancer telomere shortening mechanism intact. In this Phase I project, RTI will: 1) confirm that TERT knockout (TERT KO) and the resulting shortened telomeres exacerbate AH symptoms in the hybrid Tsukamoto-French (HTF) mouse model, the model that most closely reproduces the histologic and clinical features of AH, and 2) assess whether TERT LNPs ameliorate liver fibrosis and AH in TERT KO and wild-type mice in the HTF model. Completion of this project will demonstrate the key role of shortened telomeres in AH-related fibrosis, as well as the efficacy of TERT LNPs at extending telomeres and preventing fibrosis in a mouse model. This will pave the way for future toxicology testing to establish the preclinical safety of TERT LNPs in preparation of an IND application. Ultimately, successful development of TERT LNPs will lead to improved treatment and survival of patients with AH.Narrative Alcoholic hepatitis (AH) is a severe and acute form of alcoholic liver disease that develops in approximately one- third of chronic and heavy drinkers, is associated with high mortality, and represents a considerable healthcare and economic burden in the U.S. The standard treatment for AH, prednisolone, has not changed in over 40 years, only benefits ~50% of patients, and is associated with a significant increase in the rate of serious infections. Rejuvenation Technologies, Inc.andapos;s novel platform for therapeutic telomere extension has the potential to translate into a new and improved treatment for AH, improving patient outcomes and survival, as well as serving as a basis for a number of other therapeutic applications in which shortened telomeres have been implicated, including bone marrow failure, pulmonary fibrosis, immunodeficiency, osteoporosis, cardiovascular disease, Alzheimerandapos;s disease, and multiple types of cancer.