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CRISPRa-based rescue of sensorimotor deficits in the Scn2a+/- mouse model of autism spectrum disorder

Award Number: R01MH136475
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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CRISPRa-based rescue of sensorimotor deficits in the Scn2a+/- mouse model of autism spectrum disorder - Title: CRISPRa-based rescue of sensorimotor deficits in the Scn2a+/- mouse model of autism spectrum disorder Project Summary: Heterozygous loss-of-function mutations in the sodium channel gene SCN2A are strongly associated with autism spectrum disorder. SCN2A encodes the neuronal sodium channel NaV1.2, which contributes to membrane excitability in somatodendritic or axonal compartments, depending on cell class. Heterozygous loss of Scn2a, modeled in Scn2a+/- mice, causes deficits in cellular excitability and synaptic function across multiple brain areas, and drives robust systems- and behavioral-level deficits in sensory processing, neural coding, and sensorimotor learning. Here, our goal is to rescue these cellular, circuit and behavioral deficits using CRISPR-activation (CRISPRa)-based therapeutic approaches in Scn2a+/- mice. Most autism risk genes, like SCN2A, are associated with autism by heterozygous loss-of- function. CRISPRa is a promising therapeutic approach for many genetic forms of autism because it upregulates expression of the remaining functional gene copy, potentially rescuing cellular function. Scn2a+/- mice are an ideal test case for CRISPRa intervention in severe genetic forms of autism. We have developed CRISPRa-based reagents that restore Scn2a expression to near- normal levels, and preliminary data show that treatment of adolescent Scn2a+/- mice with CRISPRa successfully rescues cellular and synaptic phenotypes in at least one brain area. Here, we will test the effectiveness of CRISPRa rescue of cellular, circuit, and behavioral phenotypes across sensory, associative, and motor regions of the brain. To do so, we bring together three laboratories with proven expertise in Scn2a disorders and autism, cellular and systems physiology, and therapeutics. Results of this study will help establish the feasibility of gene therapy for neurodevelopmental disorders including severe genetic forms of autism, and will help define the critical developmental windows in which therapeutic interventions are most effective.


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 = $672,761 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	000	3	2/23/2026	NON-COMPETING CONTINUATION	$672,761
														Subtotal = $672,761

Issue Date FY: 2025 ( Subtotal = $672,783 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	001	2	9/23/2025	NON-COMPETING CONTINUATION	$100,918
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	000	2	2/19/2025	NON-COMPETING CONTINUATION	$571,865
														Subtotal = $672,783

Issue Date FY: 2024 ( Subtotal = $674,656 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	002	1	8/16/2024	NEW	-$15,375
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	001	1	5/15/2024	NEW	$67,465
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	000	1	3/21/2024	NEW	$622,566
														Subtotal = $674,656

Grand Total All Awards = $2,020,200

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CRISPRa-based rescue of sensorimotor deficits in the Scn2a+/- mouse model of autism spectrum disorder

Award Number: R01MH136475

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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