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Pathomechanisms of SCN3A-related neurodevelopmental disorder

Award Number: R01NS119977
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: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Pathomechanisms of SCN3A-related neurodevelopmental disorder - PROJECT SUMMARY Recently-described SCN3A-related neurodevelopmental disorder (SCN3A-NDD) is caused by pathogenic variants in the gene SCN3A, which encodes the sodium (Na+) channel subunit Nav1.3. SCN3A-NDD is a devastating condition defined by treatment-resistant epilepsy and severe/profound intellectual disability (ID); surprisingly, many patients also exhibit malformation of cortical development (MCD), a developmental disturbance in the structural formation of the cerebral cortex of the brain, suggesting functional roles for Nav1.3 during embryological development. How genetic variants in SCN3A leads to epilepsy and neurodevelopmental disability, and how SCN3A variants lead to MCD, is unknown. Research is required to clarify the functional role of Nav1.3 during early brain development and to progress towards novel therapies or preventative measures for SCN3A-NDD, which is currently and untreatable disorder. This 5-year collaborative application employs novel tools and innovative neuroscience approaches to test the hypothesis that pathogenic variants in SCN3A lead to a disorder that includes epilepsy and MCD via dysregulated Na+ currents in migrating neurons of the developing cerebral cortex. Electrophysiological recordings in heterologous cell systems indicate that pathogenic SCN3A variants found in patients with SCN3A-NDD largely produce Na+ channels that exhibit gain of function due to increased persistent current and alterations in the voltage dependence of channel activation, which increase channel activity. However, the mechanistic basis of observed variability in epilepsy severity and presence or absence of MCD, is unclear. And how altered channel activity impacts the function of neurons has not been investigated. Proposed experiments will determine the relationship between specific SCN3A variants and correlated clinical phenotype (epilepsy, MCD, severity of ID) in a large cohort of human patients with SCN3A-NDD. To link SCN3A variants to dysfunction of ion channels and neurons, we will compare the biophysical properties of normal Na+ channels to channels containing variant Nav1.3; test cell-intrinsic effects of SCN3A variants in neurons generated from induced pluripotent stem cells from human SCN3A-NDD patients; and test effects of variant overexpression via in utero electroporation of mouse embryo followed by electrical recording in brain slices (Aim 1). The impact of variant SCN3A on the morphology of immature neurons and cytoarchitecture of the developing cerebral cortex will inform the role of SCN3A in development (Aim 2). To translate these findings towards clinical applications, we will attempt to ameliorate features of SCN3A-NND in advanced model systems, including a newly generated conditional point mutant mouse, via targeted manipulation of pathogenic Nav1.3-mediated Na+ current (Aim 3). Results will provide novel information on the role of Nav1.3 during brain development, and will define the pathogenic mechanisms of SCN3A-NDD towards development of novel, targeted therapies in human patients.


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: 2025 ( Subtotal = $466,472 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/20/2024	NON-COMPETING CONTINUATION	$466,472
														Subtotal = $466,472

Issue Date FY: 2024 ( Subtotal = $523,558 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	4/25/2024	NON-COMPETING CONTINUATION	$36,281
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	4	5/9/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	12/12/2023	SUPPLEMENT FOR EXPANSION	$20,805
2024	2024	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/24/2023	NON-COMPETING CONTINUATION	$466,472
2024	2023	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	4/26/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $523,558

Issue Date FY: 2023 ( Subtotal = $536,494 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/5/2022	NON-COMPETING CONTINUATION	$528,326
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/7/2023	SUPPLEMENT FOR EXPANSION	$8,168
														Subtotal = $536,494

Issue Date FY: 2022 ( Subtotal = $580,546 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/29/2022	NON-COMPETING CONTINUATION	$58,055
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/29/2021	NON-COMPETING CONTINUATION	$522,491
														Subtotal = $580,546

Issue Date FY: 2021 ( Subtotal = $567,873 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/25/2020	NEW	$567,873
														Subtotal = $567,873

Grand Total All Awards = $2,674,943

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Pathomechanisms of SCN3A-related neurodevelopmental disorder

Award Number: R01NS119977

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: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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