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, RTI'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.
