Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Preclinical development of a precision therapy for a monogenic mental health disorder

Award Number: U01MH136567
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/16/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

Group Awards By:

View Award Description

Preclinical development of a precision therapy for a monogenic mental health disorder - PROJECT SUMMARY In this project, we propose to develop primary and secondary lead small molecules into preclinical drug candidates for a precision SYNGAP1-DEE therapy. This research is consistent with the mission of NIMH because this genetic disorder impacts mental health and behavior through impairments in intellectual and social adaptive functioning. Pathogenic SYNGAP1 variants may explain up to 1% of non-X-linked neurodevelopmental disorder cases and the estimated prevalence of these mutations is similar to that of Fragile X syndrome, or 1-4/10,000 live births. Most, if not all, SYNGAP1-DEE cases are caused by variants that lead to genetic haploinsufficiency (i.e. 50% of normal protein levels). Therefore, a rational strategy to treat these patients is to develop precision-based approaches that “boost” low SynGAP protein expression in affected brain cells. In prior NIMH funded research, we developed a novel phenotypic screening platform, NDD-ChemScreen, which can detect chemical and biological agents that raise target gene/protein expression in haploinsufficient neurons. This platform was used to discover lead small molecule compounds that substantially raise SynGAP protein. Small molecules have distinct advantages compared to other approaches for genetic disorders that impact central nervous system function. They can regulate disease- driving biology, be delivered orally and still concentrate in brain tissue, and dosing can be easily adjusted to fit individual patient needs and rapidly respond to adverse effects. While these compounds currently work well in vitro, here we will optimize through established preclinical drug development workflows. This U01 research project has three specific aims. Specific Aim 1 will focus on optimizing the primary lead, SR-1815, through medicinal chemistry. We will perform extensive SAR on SR-1815 to optimize potency, efficacy, brain penetrance, solubility, and other drug-like properties (e.g., microsomal stability, CYP inhibition) to reach a primary optimized lead. Specific Aim 2 will focus on identifying and optimizing a secondary lead series for SYNGAP1-DEE with a chemical scaffold that is distinct from the primary lead. This will de-risk the overall development of small molecules for SYNGAP1-DEE by mitigating unforeseen dead-ends that can occur during development of any given chemical scaffold. Specific Aim 3 will focus on scale-up and early-stage preclinical development of one optimized lead compound (i.e. the best of the primary or secondary optimized leads). This aim will including in vitro safety pharmacology testing and end with non- GLP dose-range finding studies in two species to determine tolerability and safety. The end result of this project will be a preclinical candidate ready for IND-enabling studies, which will be a launch pad for subsequent clinical research projects aimed at improving the quality of life for patients diagnosed with SYNGAP1-DEE.


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 = $1,781,729 )
2026	2026	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	000	3	4/6/2026	NON-COMPETING CONTINUATION	$1,781,729
														Subtotal = $1,781,729

Issue Date FY: 2025 ( Subtotal = $1,806,486 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	002	2	8/5/2025	NON-COMPETING CONTINUATION	$270,973
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	001	2	3/26/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	000	2	3/12/2025	NON-COMPETING CONTINUATION	$1,535,513
														Subtotal = $1,806,486

Issue Date FY: 2024 ( Subtotal = $1,524,504 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	001	1	6/7/2024	NEW	$152,448
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	000	1	4/16/2024	NEW	$1,372,056
														Subtotal = $1,524,504

Grand Total All Awards = $5,112,719

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Preclinical development of a precision therapy for a monogenic mental health disorder

Award Number: U01MH136567

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 04/16/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer