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Rescuing SYNGAP1 haploinsufficiency by redirecting alternative splicing

Award Number: R01MH130594
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Rescuing SYNGAP1 haploinsufficiency by redirecting alternative splicing - PROJECT SUMMARY Synaptic transmission and plasticity are fundamental to neuronal functions, and dysregulations of synaptic protein expression are direct causes of neurodevelopmental disorders such as autism. Over one hundred de novo loss-of-function mutations in SYNGAP1 have been unambiguously associated with autism spectral disorders and intellectual disability. Recent success in splice-switching oligonucleotides (SSOs) suggests that redirecting splicing through genetic and SSO-mediated ablations is a promising approach to rescue haploinsufficiency. We have identified an alternative splicing event in SYNGAP1 that leads to nonsense- mediated mRNA decay (NMD) during mouse and human development. To determine whether the SYNGAP1 NMD exon is a viable therapeutic target, we investigate the regulatory mechanism and its functions using genetic approaches, and determine whether genetic deletion and SSO suppression of the SYNGAP1 NMD exon can rescue heterozygous knockout phenotypes in mouse mutants and patient-iPSC-derived neurons. Upon completion, this project will provide genetic insights into the physiological functions of this SYNGAP1 NMD exon and generate critical preclinical reagents to restore SYNGAP1 protein expression from haploinsufficiency.


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 = $517,833 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	3	3/21/2025	NON-COMPETING CONTINUATION	$517,833
														Subtotal = $517,833

Issue Date FY: 2024 ( Subtotal = $609,214 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	001	2	8/15/2024	NON-COMPETING CONTINUATION	$60,922
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	2	3/4/2024	NON-COMPETING CONTINUATION	$548,292
														Subtotal = $609,214

Issue Date FY: 2023 ( Subtotal = $644,064 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Mental Health Research Grants	000	1	3/8/2023	NEW	$644,064
														Subtotal = $644,064

Grand Total All Awards = $1,771,111

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Rescuing SYNGAP1 haploinsufficiency by redirecting alternative splicing

Award Number: R01MH130594

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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