TERT mRNA lipid nanoparticles to extend telomeres to treat pulmonary fibrosis

TERT mRNA 脂质纳米颗粒延长端粒以治疗肺纤维化

• 批准号: 10547485
• 负责人: John Ramunas
• 金额: $ 30万
• 依托单位: REJUVENATION TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-25 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547485
• 关键词: 3-Dimensional; AGTR2 gene; Advocate; Affect; Alveolar; American; Architecture; Asphyxia; Biological; Biological Assay; Biological Markers; Bleomycin; Blood; Cell Aging; Cell Density; Cell division; Cells; Cessation of life; Chromosomes; Chronic; Collagen; Comparative Study; DNA; Defect; Diagnosis; Disease; Dose; Drug Kinetics; Encapsulated; Enzymes; Epigenetic Process; Epithelial Cells; Etiology; Exhibits; Extracellular Matrix; FDA approved; Family; Fibroblasts; Fibrosis; Frequencies; Gene Expression; Gene Expression Profile; Genomics; Grant; Half-Life; Human; Immunologic Markers; Inflammation; Inflammation Mediators; Interstitial Lung Diseases; Intravenous; Knockout Mice; Legal patent; Length; Lung; Maximum Tolerated Dose; Medical; Messenger RNA; Methods; Modeling; Molecular; Mus; Myofibroblast; Oncogenes; Oxygen; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacology and Toxicology; Phase; Pirfenidone; Pneumonia; Predisposition; Production; Prognosis; Proteins; Pulmonary Emphysema; Pulmonary Fibrosis; RNA-Directed DNA Polymerase; Rattus; Rejuvenation; Respiratory Failure; Risk; Role; S-Phase Fraction; Safety; Scientist; Serum; Silicon Dioxide; Technology; Telomerase; Telomere Shortening; Testing; Therapeutic; Time; Toxicokinetics; Transforming Growth Factor beta; Translating; Tumor-infiltrating immune cells; Universities; Validation; Work; alveolar epithelium; anti-cancer; arm; brief intervention; cell type; commercialization; delivery vehicle; density; effective intervention; epithelial stem cell; fibrotic lung; first-in-human; idiopathic pulmonary fibrosis; improved; improved outcome; in vivo; indium-bleomycin; lipid nanoparticle; loss of function mutation; lung health; lung preservation; manufacturing scale-up; meetings; mouse model; nanoparticle; nintedanib; nonhuman primate; novel strategies; pharmacodynamic biomarker; pulmonary function; senescence; side effect; single-cell RNA sequencing; standard of care; stem cells; telomere

Abstract Short telomeres, the DNA tips of chromosomes, drive multiple key pathogenic mechanisms identified in idiopathic pulmonary fibrosis (IPF) patients. Rejuvenation Technologies is developing the first safe and effective intervention to extend short telomeres in lung and thereby extend IPF patient survival. IPF is characterized by progressive scarring of lung tissue, leading to a lack of oxygen in the blood, and ultimately resulting in respiratory failure. IPF affects up to 200,000 Americans, with up to 50,000 new cases each year. IPF patients have a median survival of less than 5 years from the time of diagnosis, even with standard of care treatment. Increasing evidence, however, points to a causative role of shortened telomeres in the etiology of IPF. Loss-of-function mutations in telomerase are found in 2–5% of IPF patients and up to 15% of familial PF patients. Mice with shortened telomeres exhibit increased susceptibility to fibrosis in a mouse model of IPF. Moreover, telomere extension in mice using TERT DNA (which is not safe for humans due to the risk of genomic integration) reduces fibrosis and improves lung function. Several key pathogenic mechanisms identified in IPF patients are also consequences of critically short telomeres, including cellular senescence, elevated TGFβ and other inflammatory mediators, chronic inflammation, myofibroblast activation, loss of progenitor cells, and reduced proliferative capacity of remaining progenitor cells. These findings provide a strong rationale for developing a safe method to extend telomeres to treat IPF. RTI proposes to use lipid nanoparticles (LNPs) encapsulating TERT mRNA (TERT LNPs) to extend telomeres in the lung to treat IPF. RTI’s proprietary LNP lung delivery vehicle transfects >90% of lung epithelial cells, and a single intravenous dose of TERT mRNA in mice extends telomeres in vivo by an average of 230 bp, reversing the equivalent of years of telomere shortening in humans. Importantly for safety, TERT mRNA only increases telomerase activity for about a day, after which the extended telomeres resume shortening at their normal rate, leaving the important anti-cancer telomere shortening mechanism intact. RTI demonstrated that i.v.-injected TERT mRNA LNPs increase survival by 210%, reduce fibrosis by 68%, and improve lung function by 58% in the humanized telomere length (TERT KO) mouse bleomycin model of IPF. To advance to IND approval, this Fast Track project will complete the following Specific Aims. Phase I: 1) Pharmacokinetics (PK) and dose determination of i.v.-injected TERT mRNA LNPs. 2) Pharmacodynamics (PD), biomarker, and comparative studies to FDA approved IPF drugs. 3) Pharmacology in IPF patient cells. Phase II: 4) Determine efficacy in second mouse model (silica). 5) CMC activities for manufacturing and scale-up of TERT mRNA LNP production. 6) Perform IND-enabling toxicology and pharmacology studies. If successful, these studies will provide proof of concept of a novel approach to preserve lung function, reduce fibrosis, and extend survival in IPF. Commercialization of TERT LNPs will give IPF patients and clinicians a much-needed therapeutic option to improve outcomes and survival.

摘要 短端粒，染色体的DNA尖端，驱动着多种关键的致病机制 特发性肺纤维化(IPF)患者。年轻化科技正在开发第一个安全有效的 干预以延长肺内短端粒，从而延长IPF患者的生存期。IPF的特点是 肺组织逐渐形成疤痕，导致血液中氧气不足，最终导致呼吸系统疾病 失败了。IPF影响着多达20万美国人，每年新增病例多达5万例。IPF患者的中位数为 就算有标准的护理治疗，从确诊之日起存活也不到5年。渐增 然而，有证据表明，端粒缩短在IPF的病因中起到了致病作用。功能丧失 在2-5%的IPF患者和高达15%的家族性PF患者中发现端粒酶突变。小鼠带有 在IPF的小鼠模型中，端粒缩短显示出对纤维化的易感性增加。此外，端粒 在小鼠中使用TERT DNA(由于基因组整合的风险，这对人类不安全)的延伸可以减少 促进肺纤维化，改善肺功能。在IPF患者中发现的几个关键致病机制也是 端粒过短的后果，包括细胞衰老、转化生长因子β升高和其他炎症 介质、慢性炎症、肌成纤维细胞激活、祖细胞丢失和增殖抑制 剩余祖细胞的能力。这些发现为开发安全的方法提供了强有力的理论基础 延伸端粒治疗特发性肺纤维化。RTI建议使用脂质纳米粒(LNPs)包裹TERT mRNA(TERT LNPs)来延长肺中的端粒以治疗IPF。RTI专有的LNP肺输送载体将转染率提高到90% 在小鼠体内，单次静脉注射TERT mRNA可延长体内端粒的长度，延长端粒长度 平均230BP，逆转了相当于人类多年端粒缩短的情况。重要的是为了安全， TERT mRNA只能在大约一天的时间内增加端粒酶活性，之后延伸的端粒就会恢复 以正常的速度缩短，保持重要的抗癌端粒缩短机制不变。RTI 结果表明，静脉注射TERT mRNA LNPs可使存活率提高210%，减少68%的纤维化，以及 在人源化端粒长度(TERT KO)小鼠博莱霉素IPF模型中，肺功能改善58%。至 推进到IND批准，这个快速通道项目将完成以下具体目标。第一阶段：1) 静脉注射TERT m RNA LNPs的药代动力学和剂量测定2)药效学(PD)； 生物标志物，以及与FDA批准的IPF药物的比较研究。3)IPF患者细胞的药理学研究。第二阶段： 4)在第二种小鼠模型(硅胶模型)中测定药效。5)制造和扩大TERT的CMC活动 信使核糖核酸的产生。6)进行支持IND的毒理学和药理学研究。如果成功，这些 研究将提供一种新方法的概念证明，以保存肺功能，减少纤维化，并扩大 在IPF中存活。TERT LNPs的商业化将为IPF患者和临床医生提供急需的治疗方法 改善结果和存活率的选择。