Document text
Principal Investigator: John Ramunas
Organization: REJUVENATION TECHNOLOGIES, INC.
Fiscal Year: 2023
Award: $626,743
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Abstract
Rejuvenation Technologies Inc. (RTI) is taking the next translational step following their recent highly successful
proof-of-concept rescue of multiple mouse models that mimic key pathological features of alcoholic hepatitis
(AH). AH is an acute form of alcoholic liver disease in which the clinical response to loss of the liver’s regenerative
capacity from long-term damage includes liver failure. AH occurs in ~1/3 of heavy and chronic drinkers, and its
severity increases with the amount and duration of alcohol consumption. AH patients overall have poor
prognoses and high short-term mortality, with a 1-year survival rate of 25–50%, while those with severe AH may
show features of acute-on-chronic liver failure and exhibit a 40–50% mortality rate at 1 month from presentation.
There were over 300,000 hospital admissions for AH in 2017, and AH hospital admissions increased by over
50% during the COVID pandemic due to increased alcohol consumption that is expected to impact AH
epidemiology for years to come. The only treatments are steroids, which are ineffective at reducing patient
mortality and can increase risk of infection. There is strong evidence that short telomeres play a causal role in
AH. Telomeres are the protective DNA tips of chromosomes essential for cell and liver health. Chronic liver injury
caused by excessive alcohol consumption induces continuous hepatocyte turnover, which causes rapid telomere
shortening. When telomeres become too short, hepatocytes senesce and secrete senescence-associated
secretory phenotype factors that activate hepatic stellate cells, causing them to become fibrogenic. Transient
telomerase to extend telomeres in the liver represents a promising strategy to modify AH progression. RTI has
invented a breakthrough treatment comprising: 1) the telomere-extending biologic telomerase (TERT) mRNA
and 2) a lipid nanoparticle (LNP) vehicle that delivers mRNA to the liver with world-leading efficiency, transfecting
>99% of hepatocytes at very low doses (0.05 mg/kg), even in cirrhotic livers. During the Phase I SBIR project,
RTI demonstrated that intravenously (i.v.) injected TERT mRNA LNPs reduced high-grade inflammation by 60%,
senescence by 30%, and liver fibrosis by 38% and increased median survival by 42% in humanized telomere
length (TERT KO) mice with thioacetamide (TAA)-induced liver disease. TERT mRNA LNPs reduced liver
fibrosis by 74%, infiltrating T-cells by 33%, and DNA damage in hepatocytes by 73% in a preliminary study of an
acute-on-chronic model of AH. For Phase II, RTI will advance this product by undertaking three specific aims: 1)
investigating drug pharmacology in an acute-on-chronic liver disease model, mimicking the proposed AH clinical
treatment scenario, 2) optimizing drug product and scaling up manufacturing, and 3) piloting large animal
toxicology, pharmacokinetics, and biodistribution studies. This will provide critical efficacy and toxicology data to
support a pre-IND application, paving the way for IND-enabling studies and RTI’s first-in-human clinical trials of
TERT mRNA LNPs in AH patients. Should these prove successful, RTI will expand to other liver indications, as
shortened telomeres are a pathological hallmark of cirrhotic liver disease of any etiology.
Terms: <Acute><Alcohol Drinking><Alcohol associated hepatitis><Alcohol consumption><Alcohol hepatitis><Alcohol induced hepatitis><Alcohol related hepatitis><Alcoholic Hepatitis><Alcoholic Liver Diseases><Alcoholic liver damage><Animals><Biodistribution><Biological><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><Cancer Genes><Cancer-Promoting Gene><Causality><Cell Body><Cell division><Cells><Chromosomes><Chronic><Cirrhosis><Clinical><Clinical Treatment><Clinical Trials><DNA><DNA Damage><DNA Injury><Data><Deoxyribonucleic Acid><Disease Progression><Disease model><Dose><Drug Kinetics><Drugs><Epidemiology><EtOH drinking><EtOH use><Ethanethioamide><Ethanol-induced hepatitis><Etiology><Exhibits><Fibrosis><Genetic Alteration><Genetic Change><Genetic defect><Grant><Health><Heavy Drinking><Hepatic Cells><Hepatic Cirrhosis><Hepatic Disorder><Hepatic Failure><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatocyte><Hospital Admission><Hospitalization><Hospitals><Inflammation><Injury to Liver><Intravenous><Ito Cell><Legal patent><Length><Liver><Liver Cells><Liver Cirrhosis><Liver Failure><Liver Fibrosis><Liver diseases><Medical><Medication><Messenger RNA><Mice><Mice Mammals><Modeling><Morbidity><Morbidity - disease rate><Murine><Mus><Mutation><Natural regeneration><Oncogenes><Patents><Pathologic><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Phase><Phenotype><Play><Pre IND FDA meeting><Pre-IND mtg><Primates><Primates Mammals><Progenitor Cells><Prognosis><Proteins><Recovery><Regeneration><Regenerative capacity><Rejuvenation><Risk><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SBIR><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severities><Small Business Innovation Research><Small Business Innovation Research Grant><Steroid Compound><Steroids><Survival Rate><T cell infiltration><Technology><Technology Transfer><Telomerase><Telomere Shortening><Testing><Therapeutic Effect><Thioacetamide><Toxic effect><Toxicities><Toxicokinetics><Toxicology><Transfection><Transforming Genes><Translating><Universities><alcohol induced hepatic injury><alcohol induced liver disorder><alcohol induced liver injury><alcohol ingestion><alcohol intake><alcohol liver damage><alcohol product use><alcohol related liver disease><alcohol use><alcohol-associated liver disease><alcohol-induced hepatic damage><alcohol-induced hepatic dysfunction><alcohol-induced liver damage><alcohol-induced liver disease><alcohol-induced liver dysfunction><alcohol-mediated liver dysfunction><alcohol-mediated liver injury><alcohol-related liver disease><alcoholic beverage consumption><alcoholic drink intake><alcoholic liver injury><biologic><brief intervention><brief therapy><brief treatment><causation><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><chronic liver injury><cirrhotic><commercial scale manufacturing><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><design><designing><disease causation><disorder model><drink heavily><drug/agent><epidemiologic><epidemiological><ethanol consumption><ethanol drinking><ethanol induced hepatic injury><ethanol induced liver disorder><ethanol induced liver injury><ethanol ingestion><ethanol intake><ethanol liver disease><ethanol product use><ethanol use><ethanol-induced hepatic damage><ethanol-induced hepatic dysfunction><ethanol-induced liver damage><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><fibrotic liver><first in man><first-in-human><genome mutation><heavy alcohol use><hepatic body system><hepatic damage><hepatic disease><hepatic fibrosis><hepatic injury><hepatic organ system><hepatopathy><improved><infection risk><invention><lipid based nanoparticle><lipid nanoparticle><liver damage><liver disorder><liver injury><loss of function><lung health><mRNA><manufacture><manufacturing ramp-up><manufacturing scale-up><meeting><meetings><mortality><mouse model><murine model><non-human primate><nonhuman primate><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><pulmonary health><regenerate><regeneration ability><regeneration capacity><response><scale up batch><scale up production><senescence><senescent><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><stem cells><telomere><treatment effect><trial regimen><trial treatment><upscale manufacturing>