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Principal Investigator: Biana Godin
Organization: METHODIST HOSPITAL RESEARCH INSTITUTE
Fiscal Year: 2022
Award: $444,125
Funding agency: National Institute of Neurological Disorders and Stroke
ABSTRACT
It is estimated that annually ~3 million Traumatic brain injury (TBI) cases occur in the U.S. Moderate to severe
TBI can cause significant impairments in mental and motor functions or death. There are no effective
therapies to improve cognitive abilities after moderate-severe TBI. Many novel pharmacological approaches for
TBI therapy are not effective enough. Gene therapy can provide an unmet solution in protecting against several
neurodegenerative disorders, including TBI. Recent advances in mRNA therapeutics/ vaccines have drawn
significant attention due to their ability to tackle unmet clinical needs. For instance, the prompt development of
COVID-19 mRNA vaccines aided in controlling the pandemics worldwide. Efficient mRNA therapies require a
Lipid Nanoparticles (LNP) carrier to protect mRNA from degradation. Telomeres, repetitive non-coding DNA
sequences, have a pivotal role in tissue repair and aging. Telomere shortening in the brain results from blood
flow impairment and cell-death related inflammation and affects tissue regeneration ability. A catalytic subunit of
telomerase, an enzyme responsible for maintaining telomere length (TL) during cell division, is telomerase
reverse transcriptase (TERT). TL dysfunction has been implicated in neuroinflammatory and neurodegenerative
processes and proposed as a marker for TBI outcomes. Additionally, TERT was shown to be important in
neuronal survival and cognition, protecting from oxidative stress and blocking neuronal apoptosis. While TERT
is a potential target in neurological disorders, no studies evaluating RNA therapy to address TL in TBI were
reported yet. Here we propose a transformational therapeutic approach for TBI therapy which includes intranasal
(IN) TERT mRNA- LNP delivery to the brain. LNP protect mRNA en route to the target TBI tissue. The immediate
focus of our work is an impairment in the brain's normal function caused by an impact to the head. Our data
show that IN delivery of LNP bypasses BBB, enhancing drug transport to the brain. Our teams have
demonstrated that TERT mRNA can enhance TL in vitro and in vivo improving prognosis in other degenerative
conditions. We have also shown that there is a shortening of telomeres and reduction in TERT levels in our TBI
mouse model.
Our approach may radically change therapy for TBI, as well as other brain disorders. In this
exploratory project, our central hypothesis is that IN administration of TERT mRNA will enable temporary
expression of TERT in the affected brain tissue restoring cognitive functions after TBI. Our Specific aims are:
(1) Design, characterization, and biocompatibility of mRNA-LNP in vitro: four TERT-mRNA-LNP systems will be
designed, characterized, and assessed in vitro with various brain cells; (2) Evaluate the biodistribution and
therapeutic efficiency of IN administration of TERT mRNA-LNPs in a mouse model of TBI (Controlled cortical
impact, CCI). Biodistribution of reporter mRNA and fluorescently labeled LNP in the brains of mice with
TBI will
be performed. Efficiency will be tested based on TERT levels, TL, behavioral tests, and immunological markers.
This exploratory project can be the first step in the development of a much-needed therapy for TBI.
Terms: <Acquired brain injury><Address><Affect><Aging><Animal Model><Animal Models and Related Studies><Animals><Apoptosis><Apoptosis Pathway><Area><Attention><Bioavailability><Biodistribution><Biologic Availability><Biological Availability><Biomedical Engineering><Blood flow><Body Tissues><Brain><Brain Diseases><Brain Disorders><Brain Injuries><Brain Nervous System><Brain Trauma><Brain region><Bypass><CNS Diseases><CNS disorder><COVID-19><COVID19><CV-19><CV19><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cause of Death><Cell Body><Cell Death><Cell division><Cells><Cellular injury><Central Nervous System Diseases><Central Nervous System Disorders><Cessation of life><Chromosomal Organization><Chromosomal Structure><Chromosome Organization><Chromosome Structures><Chromosomes><Chronic><Clinical><Cognition><Cy5><DNA Damage><DNA Damage Repair><DNA Injury><DNA Repair><DNA Sequence><DNA Therapy><Data><Death><Degenerative Disorder><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Development><Diagnostic><Diffusion><Drug Transport><Drugs><Dysfunction><EC 2.7.7.49><EST2><Effectiveness><Encephalon><Encephalon Diseases><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evaluation><Event><Functional RNA><Functional disorder><Gene Transfer Clinical><Genetic Intervention><Head><Health Care Costs><Health Costs><Healthcare Costs><Hour><Immune Markers><Immunologic Markers><Impairment><In Vitro><Inflammation><Injury><Interruption><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Intranasal Administration><Intranasal Drug Administration><Knowledge><Label><Leanness><Length><Length of Life><Link><Longevity><Longitudinal Studies><Luciferase Immunologic><Luciferases><Measures><Medical><Medication><Messenger RNA><Methodology><Mice><Mice Mammals><Modeling><Modification><Morphology><Motor><Murine><Mus><Nerve Degeneration><Nervous System Degenerative Diseases><Nervous System Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Neurosciences Research><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Organ><Outcome><Oxidative Stress><Patients><Performance><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacology><Physiologic><Physiologic Availability><Physiological><Physiopathology><Play><Population><Process><Prognosis><Programmed Cell Death><Property><Proteins><Psyche structure><QOL><Quality of life><RNA><RNA Gene Products><RNA Transcriptase><RNA vaccine><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><RNA-based vaccine><Regenerative capacity><Reporter><Reporter Genes><Reporting><Reproducibility><Research><Reverse Transcriptase><Revertase><Ribonucleic Acid><Role><Route><System><TBI therapy><TBI treatment><TCS1><TERT gene><Telomerase><Telomere Reverse Transcriptase><Telomere Shortening><Testing><Therapeutic><Thinness><Tissues><Transfection><Traumatic Brain Injury><United States><Unscheduled DNA Synthesis><Untranslated RNA><Vaccines><Work><apoptosis of neuronal cells><base><behavior test><behavioral test><bio-engineered><bio-engineers><biocompatibility><bioengineering><biological engineering><biomaterial compatibility><brain cell><brain damage><brain tissue><brain-injured><cell damage><cell injury><cellular damage><cerebral vascular><cerebro-vascular><cerebrovascular><cognitive ability><cognitive disability><cognitive function><controlled cortical impact><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cyanine dye 5><damage to cells><degenerative condition><degenerative disease><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design><designing><developmental><disability><drug/agent><effective therapy><effective treatment><experience><gene repair therapy><gene therapy><gene-based therapy><genetic information><genetic therapy><genomic therapy><high reward><high risk><immune-based biomarkers><immunological biomarkers><immunological markers><improved><improved outcome><in vivo><in vivo Model><injuries><injury to cells><innovate><innovation><innovative><insight><life span><lifespan><lipid based nanoparticle><lipid nanoparticle><long-term study><longitudinal outcome studies><longterm study><mRNA><mRNA Degradation><mRNA Expression><mRNA Transcript Degradation><mRNA vaccine><mRNA-based vaccine><mental><microfluidic technology><model of animal><model organism><mouse model><multidisciplinary><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><necrocytosis><nervous system disorder><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neurological disease><neuron apoptosis><neuronal apoptosis><neuronal cells programmed cell death><neuronal degeneration><neuronal survival><neurons programmed cell death><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><noncoding><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pandemic><pandemic disease><pathophysiology><prevent><preventing><programmed cell death of neuronal cells by apoptosis><programmed cell death of neurons by apoptosis><programs><recruit><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regeneration ability><regeneration capacity><senescence><senescent><social role><synergism><telomerase catalytic subunit><telomere><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><tool><traumatic brain damage><traumatic brain injury therapy><traumatic brain injury treatment><uptake><µfluidic technology>