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 复兴技术公司(RTI)在他们最近取得巨大成功之后， 模拟酒精性肝炎关键病理特征的多种小鼠模型的概念验证拯救 （AH）。AH是一种急性酒精性肝病，其中对肝脏再生功能丧失的临床反应是 长期损害的能力包括肝功能衰竭。AH发生在约1/3的重度和慢性饮酒者中， 严重程度随着饮酒量和持续时间的增加而增加。AH患者总体表现较差 严重AH患者的1年生存率为25- 50%， 表现出慢性加急性肝衰竭的特征，并在发病后1个月表现出40-50%的死亡率。 2017年，AH的住院人数超过30万人，AH的住院人数增加了超过300，000人。 在COVID大流行期间，由于酒精消费量增加，预计将影响AH 流行病学在未来几年。唯一的治疗方法是类固醇，这是无效的，在减少病人 死亡率，并可能增加感染的风险。有强有力的证据表明，短端粒发挥因果作用， 啊端粒是细胞和肝脏健康所必需的染色体的保护性DNA尖端。慢性肝损伤 引起的过度饮酒诱导持续的肝细胞更新，这导致快速端粒 缩短。当端粒变得太短时，肝细胞衰老并分泌衰老相关的 分泌表型因子激活肝星状细胞，导致它们成为纤维化。瞬态 端粒酶在肝脏中延伸端粒代表了一种有希望的改变AH进展的策略。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，其以世界领先的效率将mRNA递送至肝脏， 在极低剂量（0.05 mg/kg）下，>99%的肝细胞，甚至在肝硬化肝脏中。在第一阶段SBIR项目期间， RTI证实静脉内（i. v.）注射的TERTmRNA LNP使高度炎症减少60%， 在人源化端粒中，衰老减少30%，肝纤维化减少38%，中位生存期增加42%。 图10显示了具有硫代乙酰胺（TAA）诱导的肝病的长（TERT KO）小鼠。TERTmRNA LNP降低肝脏 肝纤维化减少74%，浸润性T细胞减少33%，肝细胞DNA损伤减少73%。 急性-慢性AH模型对于第二阶段，RTI将通过三个具体目标来推进该产品： 在慢性加急性肝病模型中研究药物药理学，模拟拟定的AH临床 治疗方案，2）优化药物产品和扩大生产规模，以及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前申请，为IND使能研究和RTI的首次人体临床试验铺平道路。 AH患者中的TERTmRNA LNP。如果这些被证明是成功的，RTI将扩展到其他肝脏适应症， 缩短的端粒是任何病因的肝硬化疾病的病理学标志。