Document text
Principal Investigator: John Ramunas
Organization: REJUVENATION TECHNOLOGIES, INC.
Fiscal Year: 2022
Award: $299,987
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <3-D><3-Dimensional><3D><AGTR2><AGTR2 gene><AT2><Advocate><Affect><Alveolar><American><Architecture><Asphyxia><Assay><Bioassay><Biologic Assays><Biological><Biological Assay><Biological Markers><Bleo><Bleomycin><Blood><Blood Reticuloendothelial System><Blood Serum><Bone-Derived Transforming Growth Factor><Cancer Genes><Cancer-Promoting Gene><Causality><Cell Aging><Cell Body><Cell Density><Cell Proliferative Activity><Cell Senescence><Cell division><Cell-Extracellular Matrix><Cells><Cellular Aging><Cellular Proliferation Rate><Cellular Senescence><Cessation of life><Chromosomes><Chronic><Collagen><Common Rat Strains><Comparative Study><Cristobalite><DNA><Death><Defect><Deoxyribonucleic Acid><Diagnosis><Disease><Disorder><Dose><Drug Kinetics><Drugs><EC 2.7.7.49><ECM><Emphysema><Encapsulated><Engineering / Architecture><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Esbriet><Etiology><Exhibits><Expression Signature><Extracellular Matrix><FDA approved><Family><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Fibrotic lesions in lung><Frequencies><Gene Expression><Gene Expression Profile><Genomics><Grant><Half-Life><Human><Immune Markers><Immune infiltrates><Immunologic Markers><In-bleomycin><Inflammation><Inflammation Mediators><Interstitial Lung Diseases><Intravenous><KO mice><Knock-out Mice><Knockout Mice><Legal patent><Length><Lung><Lung Alveolar Epithelia><Lung Respiratory System><Lung Tissue Fibrosis><Lung scar><Lung tissue scar><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medical><Medication><Messenger RNA><Methods><Mice><Mice Mammals><Milk Growth Factor><Mitotic Index><Modeling><Modern Man><Molecular><Murine><Mus><Myofibroblast><Null Mouse><O element><O2 element><Ofev><Oncogenes><Oxygen><Patents><Pathogenicity><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Pharmacological Study><Pharmacology><Pharmacology Study><Pharmacology and Toxicology><Phase><Pirfenidone><Platelet Transforming Growth Factor><Pneumonia><Predisposition><Production><Progenitor Cells><Prognosis><Proliferation Index><Proteins><Pulmonary Emphysema><Pulmonary Fibrosis><Pulmonary Scar><Pulmonary Tissue fibrosis><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Rat><Rats Mammals><Rattus><Rejuvenation><Replicative Senescence><Respiratory Failure><Reverse Transcriptase><Revertase><Risk><Role><S-Phase Fraction><Safety><Sand><Scarring at the lung><Scarring in the lung><Scientist><Serum><Silica><Silicon Dioxide><Suffocation><Susceptibility><T cell infiltration><T cell tumor trafficking><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Technology><Telomerase><Telomere Shortening><Testing><Therapeutic><Time><Toxicokinetics><Transforming Genes><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Translating><Tridymite><Tumor-infiltrating immune cells><Universities><Validation><Work><alveolar epithelium><anti-cancer><anticancer><arm><asphyxiation><bio-markers><biologic><biologic marker><biomarker><brief intervention><brief therapy><brief treatment><causation><cell type><commercialization><delivery vector><delivery vehicle><density><diffuse interstitial pulmonary fibrosis><disease causation><drug/agent><effective intervention><emphysematous><epithelial progenitor cell><epithelial stem cell><fibrosis in the lung><fibrotic lung><first in man><first-in-human><gene expression pattern><gene expression signature><idiopathic pulmonary fibrosis><immune cell infiltrate><immune infiltration><immune-based biomarkers><immunological biomarkers><immunological markers><improved><improved outcome><in vivo><indium-bleomycin><inflammatory mediator><intratumoral immune cell><lipid based nanoparticle><lipid nanoparticle><loss of function mutation><lung failure><lung fibrosis><lung function><lung health><lung preservation><mRNA><manufacturing scale-up><meetings><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new approaches><nintedanib><non-human primate><nonhuman primate><novel approaches><novel strategies><novel strategy><pharmacodynamic biomarker><pharmacodynamic marker><pulmonary><pulmonary failure><pulmonary function><pulmonary health><scRNA-seq><senescence><senescent><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><standard of care><stem cells><telomere><three dimensional><transcriptional profile><transcriptional signature><tumor immune cell>