TERT mRNA lipid nanoparticles to extend telomeres to treat alcoholic hepatitis - Abstract
Rejuvenation Technologies Inc. (RTI) is taking the next translational step following their recent highly successful
proof-of-concept rescue of multiple mouse models that mimic key pathological features of alcoholic hepatitis
(AH). AH is an acute form of alcoholic liver disease in which the clinical response to loss of the liver’s regenerative
capacity from long-term damage includes liver failure. AH occurs in ~1/3 of heavy and chronic drinkers, and its
severity increases with the amount and duration of alcohol consumption. AH patients overall have poor
prognoses and high short-term mortality, with a 1-year survival rate of 25–50%, while those with severe AH may
show features of acute-on-chronic liver failure and exhibit a 40–50% mortality rate at 1 month from presentation.
There were over 300,000 hospital admissions for AH in 2017, and AH hospital admissions increased by over
50% during the COVID pandemic due to increased alcohol consumption that is expected to impact AH
epidemiology for years to come. The only treatments are steroids, which are ineffective at reducing patient
mortality and can increase risk of infection. There is strong evidence that short telomeres play a causal role in
AH. Telomeres are the protective DNA tips of chromosomes essential for cell and liver health. Chronic liver injury
caused by excessive alcohol consumption induces continuous hepatocyte turnover, which causes rapid telomere
shortening. When telomeres become too short, hepatocytes senesce and secrete senescence-associated
secretory phenotype factors that activate hepatic stellate cells, causing them to become fibrogenic. Transient
telomerase to extend telomeres in the liver represents a promising strategy to modify AH progression. RTI has
invented a breakthrough treatment comprising: 1) the telomere-extending biologic telomerase (TERT) mRNA
and 2) a lipid nanoparticle (LNP) vehicle that delivers mRNA to the liver with world-leading efficiency, transfecting
>99% of hepatocytes at very low doses (0.05 mg/kg), even in cirrhotic livers. During the Phase I SBIR project,
RTI demonstrated that intravenously (i.v.) injected TERT mRNA LNPs reduced high-grade inflammation by 60%,
senescence by 30%, and liver fibrosis by 38% and increased median survival by 42% in humanized telomere
length (TERT KO) mice with thioacetamide (TAA)-induced liver disease. TERT mRNA LNPs reduced liver
fibrosis by 74%, infiltrating T-cells by 33%, and DNA damage in hepatocytes by 73% in a preliminary study of an
acute-on-chronic model of AH. For Phase II, RTI will advance this product by undertaking three specific aims: 1)
investigating drug pharmacology in an acute-on-chronic liver disease model, mimicking the proposed AH clinical
treatment scenario, 2) optimizing drug product and scaling up manufacturing, and 3) piloting large animal
toxicology, pharmacokinetics, and biodistribution studies. This will provide critical efficacy and toxicology data to
support a pre-IND application, paving the way for IND-enabling studies and RTI’s first-in-human clinical trials of
TERT mRNA LNPs in AH patients. Should these prove successful, RTI will expand to other liver indications, as
shortened telomeres are a pathological hallmark of cirrhotic liver disease of any etiology.
