Preventing liver fibrosis in alcoholic hepatitis by enhancing liver regenerative capacity via transient telomere extension using lipid nanoparticle-encapsulated TERT mRNA

使用脂质纳米颗粒封装的 TERT mRNA 进行短暂端粒延伸，增强肝脏再生能力，从而预防酒精性肝炎中的肝纤维化

• 批准号: 10082259
• 负责人: John Ramunas
• 金额: $ 27.24万
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082259
• 关键词: Acute; Albumins; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alzheimer' s Disease; Animals; Apoptosis; Bile Acids; Bilirubin; Biological Assay; Blood; Blood Chemical Analysis; CDKN2A gene; Cardiovascular Diseases; Cell Aging; Cell Death; Cell division; Cells; Cerebrovascular Disorders; Chromosomes; Chronic; Cirrhosis; Clinical; DNA; DNA Damage; DNA Sequence; Data; Development; Dose; Economic Burden; Encapsulated; Exhibits; Fibrosis; Frequencies; Future; Heavy Drinking; Hepatic Stellate Cell; Hepatocyte; Histologic; Histology; Hospitals; Hour; Human; Hybrids; Immunologic Deficiency Syndromes; Impairment; In Situ Nick-End Labeling; Individual; Infection; Inflammatory; Intravenous; Knock-out; Knockout Mice; Lead; Length; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Measures; Messenger RNA; Methods; Modeling; Mus; Mutation; Myocardial Infarction; Nucleosides; Osteoporosis; Pancytopenia; Partial Hepatectomy; Patient-Focused Outcomes; Patients; Phase; Phenotype; Preparation; Proliferating; Proteins; Pulmonary Fibrosis; RNA-Directed DNA Polymerase; Regimen; Rejuvenation; Role; Safety; Stains; Steroids; Symptoms; Technology; Telomerase; Telomere Shortening; Testing; Therapeutic; Time; Toxicology; Translating; Visit; Wild Type Mouse; anti-cancer; beta-Galactosidase; cancer type; chronic liver injury; combat; cytokine; feeding; health care economics; improved; lipid nanoparticle; liver cell proliferation; mortality; mouse model; novel; novel therapeutics; preclinical safety; prednisolone; preservation; prevent; regenerative; response; senescence; standard care; stellate cell; telomere

Abstract Rejuvenation Technologies Inc. (RTI) aims to prevent liver fibrosis in alcoholic hepatitis (AH) by enhancing liver regenerative capacity. AH is an acute form of alcoholic liver disease with mortality of up to 50% within 1 month of presentation. Most AH patients exhibit advanced fibrosis/cirrhosis, which contributes to acute-on-chronic liver failure. RTI will ameliorate/prevent this fibrosis by implementing a method for the therapeutic extension of telomeres, the DNA sequences that protect chromosome ends. Telomeres naturally shorten over time and with cell division, eventually exposing the DNA end and triggering a DNA damage response that induces cell senescence and death. Accelerated telomere attrition has been identified as a plausible driver of fibrosis in AH and other fibrotic liver diseases. Thus, to combat AH-related fibrosis, RTI will use lipid nanoparticles (LNPs) to encapsulate nucleoside-modified mRNA (modRNA) encoding the telomerase reverse transcriptase (TERT) protein to transiently extend telomeres in proliferating hepatocytes. Animal studies have demonstrated the potential of this approach, as telomere extension reduces hepatocyte loss and fibrosis in a mouse model of liver cirrhosis. Moreover, RTI's preliminary results have shown that a single intravenous dose of TERT LNPs in mice extends liver telomeres by an average of 230 bp, reversing the equivalent of 5 years of telomere shortening in humans. Notably, TERT LNPs only increase telomerase activity for about 24 hours, after which the extended telomeres resume shortening at their normal rate, leaving the important anti-cancer telomere shortening mechanism intact. In this Phase I project, RTI will: 1) confirm that TERT knockout (TERT KO) and the resulting shortened telomeres exacerbate AH symptoms in the hybrid Tsukamoto-French (HTF) mouse model, the model that most closely reproduces the histologic and clinical features of AH, and 2) assess whether TERT LNPs ameliorate liver fibrosis and AH in TERT KO and wild-type mice in the HTF model. Completion of this project will demonstrate the key role of shortened telomeres in AH-related fibrosis, as well as the efficacy of TERT LNPs at extending telomeres and preventing fibrosis in a mouse model. This will pave the way for future toxicology testing to establish the preclinical safety of TERT LNPs in preparation of an IND application. Ultimately, successful development of TERT LNPs will lead to improved treatment and survival of patients with AH.

抽象的 Rejuvenation Technologies Inc. (RTI) 旨在通过增强肝脏功能来预防酒精性肝炎 (AH) 中的肝纤维化 再生能力。 AH 是一种急性酒精性肝病，1 个月内死亡率高达 50% 的演示文稿。大多数 AH 患者表现出晚期纤维化/肝硬化，这会导致慢加急性肝病 失败。 RTI 将通过实施一种延长治疗范围的方法来改善/预防这种纤维化 端粒，保护染色体末端的 DNA 序列。端粒随着时间的推移自然缩短 细胞分裂，最终暴露 DNA 末端并触发 DNA 损伤反应，从而诱导细胞分裂 衰老和死亡。端粒加速磨损已被确定为 AH 纤维化的合理驱动因素 和其他纤维化肝病。因此，为了对抗 AH 相关的纤维化，RTI 将使用脂质纳米粒子 (LNP) 封装编码端粒酶逆转录酶 (TERT) 的核苷修饰 mRNA (modRNA) 短暂延长增殖肝细胞中端粒的蛋白质。动物研究表明 这种方法的潜力，因为端粒延伸减少了小鼠肝脏模型中的肝细胞损失和纤维化 肝硬化。此外，RTI 的初步结果表明，单次静脉注射 TERT LNP 对小鼠 使肝脏端粒平均延长 230 bp，扭转了相当于 5 年的端粒缩短现象 人类。值得注意的是，TERT LNP 仅在约 24 小时内增加端粒酶活性，此后延长 端粒以正常速度恢复缩短，留下重要的抗癌端粒缩短 机制完好。在此第一阶段项目中，RTI 将：1) 确认 TERT 敲除 (TERT KO) 以及由此产生的结果 端粒缩短加剧了 Tsukamoto-French 杂交 (HTF) 小鼠模型中的 AH 症状，该模型 最接近地再现 AH 的组织学和临床特征，2) 评估 TERT LNP 是否 改善 HTF 模型中 TERT KO 和野生型小鼠的肝纤维化和 AH。该项目的完成将 证明端粒缩短在 AH 相关纤维化中的关键作用，以及 TERT LNP 的功效 在小鼠模型中延长端粒并预防纤维化。这将为未来的毒理学测试铺平道路 确定 TERT LNP 在准备 IND 申请时的临床前安全性。最终成功了 TERT LNP 的开发将改善 AH 患者的治疗和生存。