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 年轻化技术公司(RTI)在最近取得巨大成功后，正在采取下一步翻译措施 模拟酒精性肝炎关键病理特征的多只小鼠模型的概念验证拯救 (啊)。AH是一种急性形式的酒精性肝病，其临床反应是肝脏的再生能力丧失 长期损害的能力包括肝功能衰竭。约三分之一的重度和慢性饮酒者会出现AH，而且它的 严重程度随着饮酒量和饮酒时间的延长而增加。AH患者总体上有较差的 预后和较高的短期死亡率，一年存活率为25%-50%，而重度急性肝炎可能 表现为急性-慢性肝功能衰竭，发病后1个月死亡率为40%-50%。 2017年因急诊入院人数超过30万人，急诊入院人数增加超过 在COVID大流行期间，50%是由于酒精消费增加，预计会影响AH 未来几年的流行病学。唯一的治疗方法是类固醇，它不能有效地减少患者 死亡，并可能增加感染的风险。有强有力的证据表明，短端粒在 阿。端粒是染色体的保护性DNA尖端，对细胞和肝脏健康至关重要。慢性肝损伤 过量饮酒导致肝细胞持续更新，从而导致快速端粒 正在缩水。当端粒变得太短时，肝细胞衰老并分泌与衰老相关的物质 分泌表型因子，激活肝星状细胞，使其变得纤维化。瞬变 端粒酶延长肝脏中的端粒是一种很有希望的策略来改变AH的进展。RTI拥有 发明了一种突破性的治疗方法，包括：1)端粒延伸生物端粒酶(TERT)mRNA 和2)脂质纳米颗粒(LNP)载体，以世界领先的效率将mRNA输送到肝脏， 在极低剂量(0.05 mg/kg)下，99%的肝细胞，甚至在肝硬变中也是如此。在第一阶段SBIR项目中， RTI静脉注射证明了这一点。注射TERT mRNA LNPs可将高度炎症降低60%， 在人源化端粒中，衰老30%，肝纤维化38%，中位存活率提高42% 用硫代乙酰胺(TAA)诱导的小鼠肝脏疾病长度(TERT KO)。TERT mRNA LNPs降低肝脏 在一项初步研究中，肝纤维化减少了74%，T细胞浸润减少了33%，肝细胞DNA损伤减少了73% 急性-慢性-急性-慢性急性肝炎模型。对于第二阶段，RTI将通过承担三个具体目标来推进这一产品：1) 在急慢性肝病模型中研究药物药理学，模拟拟议的急性肝炎临床 治疗方案，2)优化药物生产和扩大生产，3)试验大型动物 毒理学、药代动力学和生物分布研究。这将提供关键的疗效和毒理学数据 支持IND前应用，为启用IND的研究和RTI的首个人类临床试验铺平道路 急性脑出血患者TERT基因LNPs的研究如果这些被证明是成功的，RTI将扩展到其他肝脏适应症，如 端粒缩短是任何病因的肝硬变的病理标志。