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Principal Investigator: Monica Banez-Coronel
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2023
Award: $26,239
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Repeat expansion mutations cause more than 50 neurodegenerative diseases, including Huntington’s disease
(HD) and C9orf72 amyotrophic lateral sclerosis. Despite intense research, there are no effective treatments for
any of these disorders. Repeat expansion mutations are often bidirectionally transcribed and can undergo repeat
associated non-AUG (RAN) translation (1). This process results in the expansion RNAs being translated into
toxic RAN proteins across all reading frames without the requirement for AUG, or AUG-like initiation codons (2).
Because both sense and antisense expansion RNAs can be translated in each reading frame, up to six toxic
proteins can be produced from a single mutation. RAN proteins have been reported to accumulate in disease-
affected tissues of patients for 11 expansion diseases (1, 3, 4), including Huntington’s disease (HD) (5) and
spinocerebellar ataxia type 8 (6) which are caused by CAG•CTG expansion mutations and C9orf72 which is
caused by a GGGGCC•GGCCCC expansion (7-9). There is strong evidence that RAN proteins are toxic and
contribute to a growing number of repeat-expansion disorders and could be an attractive therapeutic target.
Strong preclinical data in C9-ALS BAC transgenic mice show that passive immunotherapy reduced RAN
proteins, improved behavior, increased longevity, and improved neuropathological phenotypes including motor
neuronal survival in C9-BAC transgenic mice (10). While promising, passive immunotherapy comes with many
disadvantages including the expense to produce these antibodies and that patients must receive frequent
injections. The central hypothesis of this proposal is that vaccination against RAN proteins will be an effective
strategy to elicit a beneficial immune response and mitigate disease in C9orf72 ALS and HD mice. I propose to
test this hypothesis by determining if RNA-based liposome vaccines can elicit beneficial immune responses that
reduce RAN protein levels and improve disease in mouse models of C9-ALS and HD.
Terms: <Ab response><Affect><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Amyotrophic lateral sclerosis and frontotemporal degeneration><Amyotrophic lateral sclerosis and frontotemporal dementia><Antibodies><Antibody Affinity><Antibody Formation><Antibody Production><Antibody Response><Approaches to prevention><Autopsy><BAC clone><BACs><Bacterial Artificial Chromosomes><Behavior><Body Tissues><Brain><Brain Nervous System><C9ALS><C9ORF72><Chronic Disease><Chronic Illness><Clinical Trials><Codon><Codon Nucleotides><Combination Vaccines><Combined Vaccines><Data><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Dipeptides><Disadvantaged><Disease><Disorder><Dominantly-Inherited Spinocerebellar Ataxias><Dystrophia Myotonica><Encephalon><FTD/ALS><FTLD/ALS><Frontotemporal Lobar Degeneration/Amyotrophic lateral sclerosis><Gehrig's Disease><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Human><Huntington Chorea><Huntington Disease><Huntington's><Huntington's Disease><Huntingtons Disease><Immune mediated therapy><Immune response><Immunological response><Immunologically Directed Therapy><Immunotherapy><Individual><Initiation Codon><Initiator Codon><Injections><Lead><Length of Life><Liposomal><Liposomes><Longevity><Lou Gehrig Disease><Measures><Mice><Mice Mammals><Modern Man><Motor Cell><Motor Neurons><Murine><Mus><Mutation><Myotonia Atrophica><Myotonia Dystrophica><Myotonic Dystrophy><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Non-Polyadenylated RNA><Passive Immunotherapy><Patients><Pb element><Peptides><Phenotype><Poly A><Poly Q><Poly(rA)><Prevention approach><Process><Production><Proteins><RNA><RNA Expression><RNA Gene Products><RNA vaccine><RNA-based vaccine><Reading Frames><Reporting><Research><Ribonucleic Acid><Spinocerebellar Ataxia Type 5><Spinocerebellar Ataxia-5><Spinocerebellar Ataxias><Spinocerebellar Atrophies><Start Codon><Steinert Disease><T cell response><Testing><Tissues><Transcript><Transcription><Transgenic Mice><Translating><Translations><VAC-TX><Vaccination><Vaccine Therapy><Vaccines><amyotrophic lateral sclerosis with frontotemporal dementia><amyotrophic lateral sclerosis/FTLD><amyotrophic lateral sclerosis/frontotemporal dementia><amyotrophic lateral sclerosis/ftd><antibody biosynthesis><antigen antibody affinity><behavior phenotype><behavioral phenotyping><chromosome 9 open reading frame 72><chronic disorder><cohort><cost><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><disease phenotype><dystrophic myotonia><effective therapy><effective treatment><frontotemporal dementia-amyotrophic lateral sclerosis><frontotemporal lobar dementia amyotrophic lateral sclerosis><genome mutation><heavy metal Pb><heavy metal lead><host response><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><in vivo><insoluble aggregate><life span><lifespan><mRNA vaccine><mRNA-based vaccine><molecular phenotype><motoneuron><mouse model><murine model><necropsy><neurodegenerative illness><neuronal survival><neuropathologic><neuropathological><neuropathology><novel><passive immune therapy><passive immunotherapeutics><polyQ><polyadenylate><polyglutamine><postmortem><pre-clinical><preclinical><prevent><preventing><protein aggregate><protein aggregation><sALS><sporadic ALS><sporadic amyotrophic lateral sclerosis><therapeutic target><therapeutic vaccination><translation><vaccine antibodies><vaccine candidate><vaccine induced antibodies><vaccine response><vaccine responsiveness><vaccine-induced antibodies><vaccine-induced response>