Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by monoallelic mutation or deletion in the ( ) 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 ar...

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Published in:	eLife Vol. 11
Main Authors:	Kim, Hyojin, Gao, Eric B, Draper, Adam, Berens, Noah C, Vihma, Hanna, Zhang, Xinyuan, Higashi-Howard, Alexandra, Ritola, Kimberly D, Simon, Jeremy M, Kennedy, Andrew J, Philpot, Benjamin D
Format:	Journal Article
Language:	English
Published:	England eLife Science Publications, Ltd 10-05-2022 eLife Sciences Publications Ltd eLife Sciences Publications, Ltd
Subjects:	Analysis Animal experimentation Animals Anxiety Behavior Disease Models, Animal EEG Facies Gene deletion Gene therapy Genes Genetic aspects Genetic transcription Genetics and Genomics Genotype & phenotype Haploinsufficiency Hyperventilation Intellectual disabilities Intellectual Disability - genetics Intellectual Disability - metabolism Mice Microcephaly Mutation neurodevelopmental disorder Neurodevelopmental disorders Neurons Neuroscience Phenotype Phenotypes Physiology Pitt-Hopkins syndrome Reinstatement Rodents Transcription Factor 4 - genetics Transcription Factor 4 - metabolism Transgenic animals mouse genetics neurodevelopmental disorder neuroscience Pitt-Hopkins syndrome gene therapy genomics
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Summary:	Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by monoallelic mutation or deletion in the ( ) 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, haploinsufficiency, suggests that it could be treated by normalizing gene expression. Here, we performed proof-of-concept viral gene therapy experiments using a conditional mouse model of PTHS and found that postnatally reinstating 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Life Edit Therapeutics, Morrisville, United States. Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, United States.
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.72290