Short telomeres, the DNA tips of chromosomes, drive multiple key pathogenic mechanisms identified inidiopathic pulmonary fibrosis (IPF) patients. Rejuvenation Technologies is developing the first safe and effectiveintervention to extend short telomeres in lung and thereby extend IPF patient survival. IPF is characterized byprogressive scarring of lung tissue, leading to a lack of oxygen in the blood, and ultimately resulting in respiratoryfailure. IPF affects up to 200,000 Americans, with up to 50,000 new cases each year. IPF patients have a mediansurvival of less than 5 years from the time of diagnosis, even with standard of care treatment. Increasingevidence, however, points to a causative role of shortened telomeres in the etiology of IPF. Loss-of-functionmutations in telomerase are found in 2-5% of IPF patients and up to 15% of familial PF patients. Mice withshortened telomeres exhibit increased susceptibility to fibrosis in a mouse model of IPF. Moreover, telomereextension in mice using TERT DNA (which is not safe for humans due to the risk of genomic integration) reducesfibrosis and improves lung function. Several key pathogenic mechanisms identified in IPF patients are alsoconsequences of critically short telomeres, including cellular senescence, elevated TGFβ and other inflammatorymediators, chronic inflammation, myofibroblast activation, loss of progenitor cells, and reduced proliferativecapacity of remaining progenitor cells. These findings provide a strong rationale for developing a safe method toextend telomeres to treat IPF. RTI proposes to use lipid nanoparticles (LNPs) encapsulating TERT mRNA (TERTLNPs) 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 anaverage 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 resumeshortening at their normal rate, leaving the important anti-cancer telomere shortening mechanism intact. RTIdemonstrated that i.v.-injected TERT mRNA LNPs increase survival by 210%, reduce fibrosis by 68%, andimprove lung function by 58% in the humanized telomere length (TERT KO) mouse bleomycin model of IPF. Toadvance 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 TERTmRNA LNP production. 6) Perform IND-enabling toxicology and pharmacology studies. If successful, thesestudies will provide proof of concept of a novel approach to preserve lung function, reduce fibrosis, and extendsurvival in IPF. Commercialization of TERT LNPs will give IPF patients and clinicians a much-needed therapeuticoption to improve outcomes and survival.
Public Health Relevance Statement: Narrative
Critically short telomeres are drivers of many of the identified pathogenic mechanisms of idiopathic pulmonary
fibrosis (IPF), a disease with expected survival below five years using current standard of care. Rejuvenation is
employing mRNA encoding telomerase (TERT mRNA) to fix the telomere defect with a transient and thus safe
boost in telomerase activity, using a lipid nanoparticle (LNP) vehicle that delivers TERT mRNA to >90% of lung
epithelial cells. Telomere extension using TERT mRNA LNPs increases survival by over 200% in mice, among
many other positive effects, and this project will advance TERT mRNA LNPs to first-in-human studies within
three years.
Project Terms: 