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Understanding the role of SCN8A in developmental and epileptic encephalopathy

Award Number: R01NS131319
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/21/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Understanding the role of SCN8A in developmental and epileptic encephalopathy - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $336,056 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/31/2026	NON-COMPETING CONTINUATION	$336,056
														Subtotal = $336,056

Issue Date FY: 2025 ( Subtotal = $336,586 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/17/2025	NON-COMPETING CONTINUATION	$336,586
														Subtotal = $336,586

Issue Date FY: 2024 ( Subtotal = $374,350 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/20/2024	NEW	$374,350
														Subtotal = $374,350

Grand Total All Awards = $1,046,992

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Understanding the role of SCN8A in developmental and epileptic encephalopathy

Award Number: R01NS131319

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/21/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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