TERT mRNA lipid nanoparticles to extend telomeres to treat alcoholic hepatitis

TERT mRNA脂质纳米粒子延长端粒治疗酒精性肝炎

• 批准号: 10761603
• 负责人: John Ramunas
• 金额: $ 62.67万
• 依托单位: REJUVENATION TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761603
• 关键词: Acute; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic liver damage; Animals; Biodistribution; Biological; COVID-19 pandemic; Cell division; Cells; Chromosomes; Chronic; Cirrhosis; Clinical; Clinical Treatment; Clinical Trials; DNA; DNA Damage; Data; Disease Progression; Disease model; Dose; Drug Kinetics; Epidemiology; Etiology; Exhibits; Fibrosis; Grant; Health; Heavy Drinking; Hepatic Stellate Cell; Hepatocyte; Hospitalization; Hospitals; Inflammation; Intravenous; Legal patent; Length; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Medical; Messenger RNA; Modeling; Morbidity - disease rate; Mus; Mutation; Natural regeneration; Oncogenes; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Play; Primates; Prognosis; Proteins; Recovery; Regenerative capacity; Rejuvenation; Risk; Role; Severities; Small Business Innovation Research Grant; Steroids; Survival Rate; T cell infiltration; Technology; Technology Transfer; Telomerase; Telomere Shortening; Testing; Therapeutic Effect; Thioacetamide; Toxic effect; Toxicokinetics; Toxicology; Transfection; Translating; Universities; brief intervention; chronic liver disease; chronic liver injury; design; first-in-human; improved; infection risk; invention; lipid nanoparticle; liver injury; loss of function; lung health; manufacture; manufacturing scale-up; meetings; mortality; mouse model; nonhuman primate; pre-Investigational New Drug meeting; response; senescence; stem cells; telomere; treatment effect

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.

摘要