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

• 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
• DOI: 10.7554/eLife.72290
• EISSN: 2050-084X

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.