期刊
ELIFE
卷 11, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.72290
关键词
gene therapy; neurodevelopmental disorder; Pitt-Hopkins syndrome; Mouse
类别
资金
- Pitt Hopkins Research Foundation
- National Institute of Neurological Disorders and Stroke [R01NS114086]
- Estonian Research Council [PUTJD925]
- Orphan Disease Center [MDBR-21-105]
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutation or deletion in the TCF4 gene. Using a mouse model, researchers found that reinstating TCF4 expression improved symptoms and corrected gene abnormalities in PTHS patients.
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by monoallelic mutation or deletion in the transcription factor 4 (TCF4) gene. Individuals with PTHS typically present in the first year of life with developmental delay and exhibit intellectual disability, lack of speech, and motor incoordination. There are no effective treatments available for PTHS, but the root cause of the disorder, TCF4 haploinsufficiency, suggests that it could be treated by normalizing TCF4 gene expression. Here, we performed proof-of-concept viral gene therapy experiments using a conditional Tcf4 mouse model of PTHS and found that postnatally reinstating Tcf4 expression in neurons improved anxiety-like behavior, activity levels, innate behaviors, and memory. Postnatal reinstatement also partially corrected EEG abnormalities, which we characterized here for the first time, and the expression of key TCF4-regulated genes. Our results support a genetic normalization approach as a treatment strategy for PTHS, and possibly other TCF4-linked disorders.
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