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.

抽象的 短端粒（染色体的DNA尖端）驱动多种关键的致病机制 特发性肺纤维化（IPF）患者。恢复活力技术正在开发第一个安全有效的 干预措施以扩展肺部短端粒，从而扩展IPF患者的生存。 IPF的特征是 肺组织的进行性疤痕，导致血液中缺乏氧气，最终导致呼吸道 失败。 IPF影响多达200,000名美国人，每年最多有50,000例新案件。 IPF患者的中位数 即使接受护理标准治疗，从诊断开始就不到5年。增加 然而，证据表明，端粒缩短在IPF的病因中的病因作用。功能丧失 在2-5％的IPF患者和多达15％的家庭PF患者中发现了端粒酶突变。老鼠与 在IPF的小鼠模型中，暴露的端粒缩短了对纤维化的敏感性。而且，端粒 使用TERT DNA（由于基因组整合的风险而对人类不安全的小鼠延伸）降低 纤维化并改善肺功能。在IPF患者中发现的几种关键致病机制也是 关键的短端粒的后果，包括细胞感应，TGFβ升高和其他炎症 介体，慢性炎症，肌纤维细胞激活，祖细胞的丧失并减少增殖 剩余祖细胞的能力。这些发现为开发一种安全的方法提供了有力的理由 扩展端粒以治疗IPF。 RTI使用脂质纳米颗粒（LNP）封装TERT mRNA的提议（TERT LNP）扩展肺中的端粒以治疗IPF。 RTI的专有LNP肺输送车> 90％ 肺上皮细胞和小鼠中单次静脉剂量的TERT mRNA通过一个在体内扩展端粒 平均为230 bp，逆转了人类的端粒缩短年份。重要的是为了安全 TERT mRNA仅增加端粒酶活性大约一天，然后扩展的端粒恢复 以正常速度缩短，使重要的抗癌端粒缩短机制完整。 RTI 证明注射静脉注射的TERT mRNA LNP将存活率提高210％，将纤维化降低68％，并且 IPF的人源化端粒长度（TERT KO）小鼠博来霉素模型中的肺功能提高了58％。到 提前获得IND批准，这个快速轨道项目将完成以下特定目标。第一阶段：1） 注射的tert mRNA LNP的药代动力学（PK）和剂量测定。 2）药效学（PD）， 生物标志物和FDA批准的IPF药物的比较研究。 3）IPF患者细胞中的药理学。第二阶段： 4）确定第二小鼠模型（二氧化硅）的效率。 5）用于制造和扩大TERT的CMC活动 mRNA LNP生产。 6）进行毒理学和药理学研究。如果成功，这些 研究将提供一种新型方法的概念证明，以保持肺功能，减少纤维化并扩展 IPF的生存。 TERT LNP的商业化将为IPF患者和临床医生提供急需的治疗 改善预后和生存的选项。