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Principal Investigator: Jacy Lee Wagnon
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $374,350
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Developmental and epileptic encephalopathies (DEEs) are severe early-onset seizure disorders with
treatment-resistant seizures, developmental delay/regression, and long-term cognitive and motor impairment.
SCN8A DEE, caused by gain-of-function, missense variants in the voltage-gated sodium channel gene SCN8A
(Nav1.6), is characterized by infantile-onset seizures, mild to severe intellectual disability, significant
developmental delay, and elevated risk of premature lethality. A serious comorbidity in SCN8A DEE is the
prominent motor impairment, including severe hypotonia, movement disorders, and a large proportion of
individuals that are non-ambulatory. Two mouse models carrying the patient mutations p.Asn1768Asp
(N1768D) or p.Arg1872Trp (R1872W) recapitulated seizures and early death but did not exhibit motor
impairment. Thus, insight into the mechanisms underlying motor impairment in SCN8A DEE has not previously
been possible. We developed a novel conditional mouse model of SCN8A DEE with the patient mutation
p.Thr767Ile (T767I). The T767I mouse is the first model of SCN8A DEE that exhibits significant muscle
weakness and motor impairment. Our preliminary data suggests that functional motor units are reduced in
Scn8a-T767I/+ mice. We hypothesize that the Scn8a-T767I mutation alters spinal motor neuron activity,
leading to dysfunction of the motor unit and motor impairment in SCN8A DEE. Thus, we propose to use this
unique mouse model to address the gap in our understanding of the pathophysiology underlying motor
impairment in SCN8A DEE. We will use the T767I mouse to 1) determine how Scn8a-T767I affects motor unit
structure, function and connectivity, 2) determine how expression of Scn8a-T767I in motor neurons affects
neuromotor development, and 3) determine whether motor impairment can be prevented or reversed with
administration of an anti-sense oligonucleotide that reduces expression of Scn8a in brain and spinal cord.
Information gained from these studies will provide mechanistic insight into the pathophysiology of SCN8A DEE
that will aid in the development of new therapeutic strategies for this severe disorder.
Terms: <ASO therapeutics><ASO therapy><ASO treatment><Abnormal Movements><Action Potentials><Address><Affect><Age><Antisense Agent><Antisense Oligonucleotide Therapy><Antisense Oligonucleotides><Aran-Duchenne disease><Architecture><Ataxia><Ataxy><Axon><Behavior assessment><Biophysics><Brain><Brain Nervous System><Cessation of life><Characteristics><Clinical><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Convulsive Seizures><Coordination Impairment><Cruveilhier disease><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Decreased Muscle Tone><Development><Developmental Delay><Developmental Delay Disorders><Disease><Disorder><Disturbance in cognition><Dysfunction><Dyskinesia Syndromes><Dyskinesias><Dyskinetic syndrome><Dyssynergia><Dystonia><Electrophysiology><Electrophysiology (science)><Encephalon><Engineering / Architecture><Epilepsy><Epileptic Seizures><Epileptics><Exhibits><Fore-Brain><Forebrain><Functional disorder><Gene variant><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Heterozygote><Histology><Hypomyotonia><Hypotonia><Impaired cognition><Impairment><Incidence><Individual><Injections><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Maintenance><Measures><Medulla Spinalis><Mice><Mice Mammals><Modeling><Morphology><Motor><Motor Cell><Motor Neurons><Motor Seizures><Movement Disorder Syndromes><Movement Disorders><Murine><Mus><Muscle><Muscle Dystonia><Muscle Fibers><Muscle Hypotony><Muscle Tissue><Muscle Tone Poor><Muscle Weakness><Muscle hypotonia><Muscular Hypotonia><Muscular Weakness><Mutation><Myoneural Junction><Myotubes><NAV1.6><NaCh6><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuromuscular Junction><Neurons><Neurophysiology / Electrophysiology><Pathogenesis><Pathology><Patients><Phenotype><Physiopathology><Population><Prosencephalon><QOL><Quality of life><Recurrence><Recurrent><Reporting><Resistance><Rhabdomyocyte><Risk><Role><SCN8A><SCN8A gene><Seizure Disorder><Seizures><Sequence Alteration><Skeletal Fiber><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Sodium Channel><Sodium Ion Channels><Specific Child Development Disorders><Spinal><Spinal Cord><Spinal Muscular Atrophy><Structure><Tamoxifen><Testing><Therapeutic><Time><Variant><Variation><Work><ages><allele variant><allelic variant><anti-sense oligonucleotide drug><anti-sense oligonucleotide therapy><anti-sense oligonucleotide treatment><anti-sense therapy><antisense drug><antisense oligo><antisense oligonucleotide therapeutic><antisense therapeutics><antisense therapy><behavior test><behavioral assessment><behavioral test><biophysical foundation><biophysical principles><biophysical sciences><co-morbid><co-morbidity><cognitive dysfunction><cognitive loss><comorbidity><develop therapy><developmental><early onset><early onset disorder><electrophysiological><epilepsia><epileptic encephalopathies><epileptogenic><excitatory neuron><experiment><experimental research><experimental study><experiments><gain of function><genetic variant><genome mutation><genomic alteration><genomic variant><heterozygosity><improved><infancy><infantile><innervation><insight><intellectual and developmental disability><intervention development><limited intellectual functioning><motoneuron><motor control><motor disease><motor disorder><motor dysfunction><motor impairment><mouse model><movement impairment><movement limitation><murine model><muscular><nerve cell death><nerve cell loss><nerve supply><neuromuscular><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal excitability><neuronal loss><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pharmacologic><postnatal><premature><prematurity><prevent><preventing><resistant><severe intellectual disability><social role><sodium channel, voltage gated, type VIII, alpha subunit><therapy development><treatment development><voltage>