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 app...