Advancing a telomere extension biologic to treat alcohol-associated liver damage to IND

About This Grant

Abstract Rejuvenation Technologies Inc. (RTI) seeks to continue advancing the translation of a telomere extension biologic, TERT mRNA, which is delivered to the liver intravenously (i.v.) using hepatocyte-targeted lipid nanoparticles (LNPs) for the treatment of alcoholic hepatitis (AH). AH is an acute form of alcoholic liver disease (ALD) that represents a dire unmet medical need, as mortality within 1 month of presentation is 25–50%. Most AH patients exhibit advanced fibrosis/cirrhosis, contributing to acute-on-chronic liver failure. The only definitive treatments are steroids, which are ineffective at reducing patient mortality. However, there is strong evidence that short telomeres play a casual role in AH. Telomeres, the protective DNA tips of chromosomes shorten with each cell division; chronic liver injury due to excessive alcohol consumption drives compensatory hepatocyte proliferation resulting in rapid telomere shortening, hepatocytic senescence, and the secretion of senescence- associated secretory phenotype factors that activate hepatic stellate cells, causing them to become fibrogenic. Short telomeres limit the ability of hepatocytes to divide and the liver to regenerate, ultimately leading to liver failure. RTI’s team has invented a breakthrough treatment addressing shortening telomeres in AH patients comprising 1) the telomere-extending biologic telomerase (TERT) mRNA and 2) an LNP vehicle that delivers mRNA to the liver with high efficiency, transfecting >99% of hepatocytes at very low doses (0.05 mg/kg), with high transfection even in cirrhotic livers. Upon delivery to the cells, TERT mRNA is translated to functional TERT protein, and both are degraded within days. During this brief treatment, telomeres are extended sufficiently to reverse years of telomere shortening. After the TERT degrades, telomeres resume shortening normally. TERT mRNA does not immortalize cells, and TERT is not an oncogene. RTI’s TERT mRNA LNPs are a highly effective, low risk, revolutionary biologic to improve and extend the lives of AH patients. A prior NIAAA Phase II SBIR and an INTERACT meeting on AH with the FDA has led to this proposed Commercialization Readiness Pilot (CRP) that will culminate in an IND submission. The specific aims are: 1) Pharmacokinetic (PK) study of mRNA and select lipids in mice to measure rate of clearance; 2) Pre-treatment evaluation in mice; 3) GMP manufacturing, genotoxicity studies, and IND-enabling GLP toxicology studies in NHPs; and 4) Preparation of IND data package and FDA submission.