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