Document text
Principal Investigator: John Ramunas
Organization: REJUVENATION TECHNOLOGIES, INC.
Fiscal Year: 2020
Award: $272,403
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Abstract
Rejuvenation Technologies Inc. (RTI) aims to prevent liver fibrosis in alcoholic hepatitis (AH) by enhancing liver
regenerative capacity. AH is an acute form of alcoholic liver disease with mortality of up to 50% within 1 month
of presentation. Most AH patients exhibit advanced fibrosis/cirrhosis, which contributes to acute-on-chronic liver
failure. RTI will ameliorate/prevent this fibrosis by implementing a method for the therapeutic extension of
telomeres, the DNA sequences that protect chromosome ends. Telomeres naturally shorten over time and with
cell division, eventually exposing the DNA end and triggering a DNA damage response that induces cell
senescence and death. Accelerated telomere attrition has been identified as a plausible driver of fibrosis in AH
and other fibrotic liver diseases. Thus, to combat AH-related fibrosis, RTI will use lipid nanoparticles (LNPs) to
encapsulate nucleoside-modified mRNA (modRNA) encoding the telomerase reverse transcriptase (TERT)
protein to transiently extend telomeres in proliferating hepatocytes. Animal studies have demonstrated the
potential of this approach, as telomere extension reduces hepatocyte loss and fibrosis in a mouse model of liver
cirrhosis. Moreover, RTI's preliminary results have shown that a single intravenous dose of TERT LNPs in mice
extends liver telomeres by an average of 230 bp, reversing the equivalent of 5 years of telomere shortening in
humans. Notably, TERT LNPs only increase telomerase activity for about 24 hours, after which the extended
telomeres resume shortening at their normal rate, leaving the important anti-cancer telomere shortening
mechanism intact. In this Phase I project, RTI will: 1) confirm that TERT knockout (TERT KO) and the resulting
shortened telomeres exacerbate AH symptoms in the hybrid Tsukamoto-French (HTF) mouse model, the model
that most closely reproduces the histologic and clinical features of AH, and 2) assess whether TERT LNPs
ameliorate liver fibrosis and AH in TERT KO and wild-type mice in the HTF model. Completion of this project will
demonstrate the key role of shortened telomeres in AH-related fibrosis, as well as the efficacy of TERT LNPs at
extending telomeres and preventing fibrosis in a mouse model. This will pave the way for future toxicology testing
to establish the preclinical safety of TERT LNPs in preparation of an IND application. Ultimately, successful
development of TERT LNPs will lead to improved treatment and survival of patients with AH.
Terms: <1,2-Dehydrohydrocortisone><AD dementia><Acute><Albumins><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcoholic beverage heavy drinker><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimers Dementia><Alzheimers disease><Animals><Apoptosis><Apoptosis Pathway><Assay><Bile Acids><Bilirubin><Bilirubin IX alpha><Bioassay><Biologic Assays><Biological Assay><Blood><Blood Chemical Analyses><Blood Chemical Analysis><Blood Reticuloendothelial System><Bone marrow failure><Brain Vascular Disorders><CDK4I><CDKN2><CDKN2 Genes><CDKN2A><CDKN2A gene><CMM2><Cardiac infarction><Cardiovascular Diseases><Cell Aging><Cell Body><Cell Death><Cell Senescence><Cell division><Cells><Cellular Aging><Cellular Senescence><Cerebrovascular Disease><Cerebrovascular Disorders><Chromosomes><Chronic><Cirrhosis><Clinical><Cyclin-Dependent Kinase Inhibitor 2A Gene><DNA><DNA Damage><DNA Injury><DNA Sequence><Data><Delta(1)Hydrocortisone><Delta-F><Delta1-dehydro-hydrocortisone><Deltahydrocortisone><Deoxyribonucleic Acid><Development><Dose><EC 2.7.7.49><Economic Burden><Encapsulated><Ethanol-induced hepatitis><Exhibits><Fibrosis><Frequencies><Future><Genetic Alteration><Genetic Change><Genetic defect><Heavy Drinker><Heavy Drinking><Hepatic Cells><Hepatic Cirrhosis><Hepatic Disorder><Hepatic Failure><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatocyte><Histologic><Histologically><Histology><Hospitals><Hour><Human><Hybrids><INK4><INK4A><Immunodeficiency Disorder><Immunodeficiency Syndrome><Immunologic Deficiency Syndromes><Immunological Deficiency Syndromes><Impairment><In Situ Nick-End Labeling><Individual><Infection><Inflammatory><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Intravenous><Ito Cell><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lead><Length><Liver><Liver Cells><Liver Cirrhosis><Liver Failure><Liver Fibrosis><Liver diseases><MTS1><MTS1 Genes><Measures><Messenger RNA><Metacortandralone><Methods><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Mutation><Myocardial Infarct><Myocardial Infarction><Nucleosides><Null Mouse><Osteoporosis><Pancytopenia><Partial Hepatectomy><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Phase><Phenotype><Prednisolonum><Preparation><Primary Senile Degenerative Dementia><Programmed Cell Death><Proliferating><Proteins><Pulmonary Fibrosis><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Regimen><Rejuvenation><Replicative Senescence><Reverse Transcriptase><Revertase><Role><Safety><Staining method><Stains><Steroid Compound><Steroids><Symptoms><TP16><TSG9A><TUNEL><Technology><Telomerase><Telomere Shortening><Testing><Therapeutic><Time><Toxicology><Translating><Visit><Wild Type Mouse><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol-induced hepatic dysfunction><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcoholic liver injury><anti-cancer><anticancer><beta-D-Galactosidase><beta-D-Galactoside galactohydrolase><beta-Galactosidase><blood chemistry><brain vascular disease><brain vascular dysfunction><cancer type><cardiac infarct><cardiovascular disorder><cerebral vascular disease><cerebral vascular dysfunction><cerebrovascular dysfunction><chronic liver injury><cirrhotic><combat><coronary attack><coronary infarct><coronary infarction><cytokine><dementia of the Alzheimer type><developmental><drink heavily><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol-induced hepatic dysfunction><ethanol-induced liver disease><ethanol-induced liver dysfunction><ethanol-mediated liver dysfunction><ethanol-mediated liver injury><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><extreme drinking><feeding><fibrotic liver><genome mutation><health care economics><healthcare economics><heart attack><heart infarct><heart infarction><heavy alcohol use><heavy metal Pb><heavy metal lead><hepatic body system><hepatic cell proliferation><hepatic cellular proliferation><hepatic disease><hepatic fibrosis><hepatic organ system><hepatocyte cell proliferation><hepatocyte cellular proliferation><hepatocyte proliferation><hepatopathy><hypoimmunity><immune deficiency disorder><immunodeficiency><improved><intracranial vascular dysfunction><lac Z Protein><lipid nanoparticle><liver cell proliferation><liver cellular proliferation><liver disorder><lung fibrosis><mRNA><mortality><mouse model><murine model><necrocytosis><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><p14ARF><p16 Genes><p16INK4 Genes><p16INK4A Genes><p16INK4a><partial excision of liver><pre-clinical safety><preclinical safety><prednisolone><preservation><prevent><preventing><primary degenerative dementia><regenerative><response><senescence><senescent><senile dementia of the Alzheimer type><social role><standard care><standard treatment><stellate cell><subtotal hepatectomy><telomere><terminal nick end labeling><wildtype mouse><β-D-Galactosidase><β-D-Galactoside galactohydrolase><β-Galactosidase>