Juvenile reinstatement of TCF4 in Pitt-Hopkins syndrome model mice reveals a critical window for genetic intervention

ABSTRACT Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of TCF4 which encodes transcription factor 4. As PTHS therapeutics advance toward clinical trials, identifying the optimal timing for treatment is crucial. Our previous research demonstrated that restoring TCF4 during embryonic or neonatal stages, corresponding to prenatal or neonatal periods in humans, improved phenotypes in a PTHS mouse model (Kim et al., 2022). However, PTHS diagnosis generally occurs much later, when infants fail to reach developmental milestones and undergo genetic testing. This raises an essential question: can genetic therapeutics initiated at more clinically relevant time points retain effectiveness? Here, we examined whether reinstating TCF4 in juvenile PTHS model mice could reverse behavioral phenotypes, simulating a gene therapy. Our findings indicate that this delayed intervention largely fails to correct most phenotypes, except for a measure of cognitive function. These results reveal phenotype-specific plasticity and underscore a narrow, early critical window for effective treatment in PTHS. Our study also identifies the hippocampus as a potential target for PTHS therapeutics and suggests that while some cognitive functions may still retain therapeutic plasticity, reversing most core PTHS symptoms may require intervention during the very early postnatal, or potentially prenatal periods, in humans. Competing Interest Statement BDP is a consultant for Astellas Gene Therapies.