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Principal Investigator: John Ramunas
Organization: REJUVENATION TECHNOLOGIES, INC.
Fiscal Year: 2024
Award: $520,303
Funding agency: National Center for Advancing Translational Sciences
Abstract
Rejuvenation Technologies Inc. (RTI) seeks to improve the tools required for clinical translation of intravenously-
infused RNA lipid nanoparticle (LNP) therapeutics. While there is abundant work on RNA LNP vaccines, the
requirements for intravenously-infused LNPs are significantly more demanding, because instead of causing an
immune response as with a vaccine, IV-infused LNPs must avoid an immune response. Immune responses can
be caused by the RNA or the LNP components, and can lead to adaptive immunity, autoimmunity, anaphylactic
shock, desensitization or sensitization, and reduced drug potency with repeat dosing. As a test case, RTI will
focus on their telomere extension biologic, which has shown highly successful proof-of-concept rescue of
multiple mouse models of liver and lung disease. Telomeres are the protective DNA tips of chromosomes.
Telomeres shorten with each cell division, eventually exposing the DNA tip, causing genome instability and
progenitor cell apoptosis or senescence. This diminishes the regenerative capacity of organs, driving a number
of pathological conditions that include aging-related diseases like lung, kidney, and liver fibrosis, and bone
marrow failure. Thus, telomere extension represents a promising strategy for regenerative medicine. RTI’s
solution is to extend critically short telomeres by transiently increasing TERT levels via targeted delivery of
modified TERT mRNA in biodegradable lipid nanoparticles (LNPs). RTI has multiple LNPs capable of delivering
mRNA to the lung or liver with world- leading efficiency, transfecting >90% of target cells, even in diseased
organs. Upon delivery to cells, TERT mRNA is translated to functional TERT protein, and both are degraded
within days, yet telomeres are extended sufficiently to reverse years of shortening. Preliminary work has shown
the strong potential benefits of the TERT therapy in models of both liver and lung fibrosis. Moreover, RTI has
developed broadly transfecting-LNPs capable of transfecting 16 tissues in non-human primates, opening the
door to extra-hepatic extra-pulmonary mRNA delivery. In the future, RTI intends to add targeting ligands,
conferring additional cell type-specificity and enabling the extension of these results to other forms of disease.
In this Direct to Phase II project, RTI seeks to develop a platform that can be used for efficient translation and
manufacturing following FDA’s chemistry, manufacturing, and controls guidelines of TERT mRNA LNP therapies
from preclinical models to the clinic. To do so, RTI will undertake four specific aims: 1) high-sensitivity drug-
specific analytical capability development, 2) high-sensitivity cell-type-specific biodistribution, 3) evaluating drug
component stability, and 4) high-sensitivity bioanalytical methods for identifying drug breakdown products. These
studies will provide the high-sensitivity methods critical for clinical translation of intravenously-infused RNA LNP
therapeutic drug products. As a specific use case, these studies will support translation of RTI’s TERT mRNA
LNPs for multiple clinical indications with dire unmet medical need.
Terms: <Acceleration><Acute><Aging><Alcohol associated hepatitis><Alcohol hepatitis><Alcohol induced hepatitis><Alcohol related hepatitis><Alcoholic Hepatitis><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Animal Model><Animal Models and Related Studies><Animal Testing><Apoptosis><Apoptosis Pathway><Assay><Autoimmune Status><Autoimmunity><Automobile Driving><Bioassay><Biodistribution><Biological><Biological Assay><Biology><Bleo><Bleomycin><Body Tissues><Bone marrow failure><Cancer Genes><Cancer-Promoting Gene><Cancers><Capillary Electrophoresis><Capillary Electrophoresis Fractionation><Cell Body><Cell division><Cells><Chemistry><Chromosomes><Chronic><Clinic><Clinical><Clinical Trials><Closure by Ligation><Cryo-electron Microscopy><Cryoelectron Microscopy><DNA><DNA Damage><DNA Injury><Data><Deoxyribonucleic Acid><Development><Disease><Disorder><Dose><Double-Stranded RNA><Drug Stability><Drugs><Electron Cryomicroscopy><Ethanethioamide><Ethanol-induced hepatitis><Evaluation><Extrahepatic><Feedback><Fibrosing Alveolitis><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Genes><Genome Instability><Genomic Instability><Grant><Guidelines><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatocyte><IV Infusion><Immune response><Immunological response><Intravenous><Intravenous infusion procedures><Legal patent><Length><Licensing><Ligands><Ligation><Lipids><Liver><Liver Cells><Liver Fibrosis><Liver diseases><Lung><Lung Diseases><Lung Respiratory System><Lung Tissue Fibrosis><Malignant Neoplasms><Malignant Tumor><Measures><Medical><Medication><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Murine><Mus><Non-Polyadenylated RNA><Oncogenes><Organ><Patents><Pathologic><Patients><Pharmaceutical Preparations><Phase><Plasmids><Poly A><Poly(rA)><Pre-Clinical Model><Preclinical Models><Production><Progenitor Cells><Programmed Cell Death><Proteins><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Regenerative Medicine><Regenerative capacity><Rejuvenation><Ribonucleic Acid><Risk><Safety><Specificity><T cell infiltration><Technology><Telomerase><Telomere Shortening><Temperature><Testing><Therapeutic><Thioacetamide><Time><Tissues><Transfection><Transforming Genes><Translating><Translations><Universities><Vaccines><Work><Wound Repair><adaptive immunity><age associated disease><age associated disorder><age associated impairment><age dependent disease><age dependent disorder><age dependent impairment><age related human disease><age-related disease><age-related disorder><age-related impairment><aging associated disease><aging related disease><biologic><brief intervention><brief therapy><brief treatment><cell type><clinical translation><clinically translatable><cryo-EM><cryoEM><cryogenic electron microscopy><deliver mRNA><deliver messenger RNA><delivery system for mRNA><desensitization><developmental><diffuse interstitial pulmonary fibrosis><disease model><disease of aging><disease of the lung><disorder model><disorder of aging><disorder of the lung><driving><drug sensitivity><drug/agent><dsRNA><fibrosis in the lung><fibrotic liver><first in man><first-in-human><flow cytophotometry><hepatic body system><hepatic disease><hepatic fibrosis><hepatic inflammation><hepatic organ system><hepatopathy><host response><idiopathic pulmonary fibrosis><immune system response><immunoresponse><improved><inflamed liver><innovate><innovation><innovative><intravenous infusion><invention><kidney fibrosis><lipid based nanoparticle><lipid nanoparticle><liver disorder><liver inflammation><lung disorder><lung fibrosis><lung function><mRNA><mRNA delivery><mRNA vaccine><mRNA-based vaccine><malignancy><manufacture><messenger RNA delivery><model of animal><mouse model><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><nanoparticle drug><nanoparticle therapy><neoplasm/cancer><non-human primate><nonhuman primate><novel><polyadenylate><prevent><preventing><pulmonary><pulmonary function><regeneration ability><regeneration capacity><regenerative approach><regenerative strategy><regenerative technique><renal fibrosis><scRNA-seq><senescence><senescent><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><site targeted delivery><stem cells><targeted delivery><telomere><telomere attrition><therapeutic nanoparticles><tool><translation><translational applications><wound healing><wound recovery><wound resolution>