Saturday, July 5, 2025 7/5/2025

Investigation of Pitt-Hopkins Syndrome pathophysiology using a human model

Award Number: R01MH123828
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/05/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

Group Awards By:

View Award Description

Investigation of Pitt-Hopkins Syndrome pathophysiology using a human model - PROJECT SUMMARY Autism-spectrum disorders impact millions of individuals worldwide, representing a heavy toll on affected children, their families, and the health care system. Pitt–Hopkins Syndrome (PTHS) is an ASD caused by de novo mutations in the TCF4 gene. PTHS is characterized by severe intellectual disability, pronounced developmental and motor delays, absence of speech, repetitive behaviors, peculiar facial gestalt, and gastrointestinal manifestations. While the genetic etiology of PTHS is well established, the cellular and neural phenotypic alterations in human patients are still not fully understood, nor is it clear how TCF4 mutations cause such abnormalities. Lack of understanding about PTHS's molecular and cellular mechanisms is a problem because, until this information becomes available, specific altered pathways cannot be therapeutically targeted. Moreover, without neuropathological knowledge, it is impossible to treat and eventually cure PTHS by directly correcting the mutation in the genome. Our long-term goal is to understand how specific genetic defects and altered pathways in the brain result in the debilitating phenotypes exhibited by autistic children. The objectives of this application are to: (a) use human models of neural development in vitro to define the cellular and neural pathological consequences of clinically relevant TCF4 mutations in PTHS; and (b) provide proof-of-concept that correctional molecular strategies can be used to fix TCF4 expression, an approach that could eventually be used as gene therapy for PTHS. Our central hypothesis is that TCF4 mutations cause aberrant phenotypes in specific cell types of the nervous system, leading to the patients' neurological symptoms. We postulated that patient-derived in vitro models of PTHS can better recapitulate the pathophysiology than mouse models, because brain structure, genome architecture and development vary greatly between rodents and humans, and current PTHS animal models do not closely mimic all the disease's clinically relevant aspects. In preliminary experiments, we obtained patient-derived brain organoids and cultured neural cell types in vitro and used them as human models to show that PTHS neural progenitor cells exhibit senescence and decreased proliferation, accompanied by downregulation of Wnt signaling and SOX3 expression. Moreover, we observed that PTHS brain organoids fail to develop normal anatomically organized progenitor structures and that PTHS neurons display severely impaired firing properties. Our anticipated results/deliverables include the identification and manipulation of specific altered molecular pathways and neural cell types and the testing of genetic correctional strategies for the disease, which could propel future research on pharmacological and gene therapy for PTHS.


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 = $335,750 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	5	12/10/2024	NON-COMPETING CONTINUATION	$335,750
														Subtotal = $335,750

Issue Date FY: 2024 ( Subtotal = $395,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	001	4	8/14/2024	NON-COMPETING CONTINUATION	$39,500
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	4	1/12/2024	NON-COMPETING CONTINUATION	$355,500
														Subtotal = $395,000

Issue Date FY: 2023 ( Subtotal = $395,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	3	1/19/2023	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2022 ( Subtotal = $395,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	2	1/21/2022	NON-COMPETING CONTINUATION	$355,500
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	001	2	6/7/2022	NON-COMPETING CONTINUATION	$39,500
														Subtotal = $395,000

Issue Date FY: 2021 ( Subtotal = $394,479 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Mental Health Research Grants	000	1	3/5/2021	NEW	$394,479
														Subtotal = $394,479

Grand Total All Awards = $1,915,229

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Investigation of Pitt-Hopkins Syndrome pathophysiology using a human model

Award Number: R01MH123828

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/05/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer