Better together: a Multi-model Approach for Pitt-Hopkins syndrome

Scientific research uses many model systems to try to understand the biological and molecular bases of many pathologies including rare genetic diseases. Each scientist specializes in one or more experimental models but with the awareness that there is no perfect model to answer all the questions. By combining the expertise of national and international scientists and various model systems - zebrafish, mice, and human cerebellar organoids - we aim to leverage the unique advantages each model offers, providing a more comprehensive understanding of the biological and molecular mechanisms altered in Pitt-Hopkins Syndrome (PTHS). This collaborative and interdisciplinary approach has significant potential to yield new insights into this rare genetic disease and promote the development of innovative therapeutic strategies. Our project focusing on PTHS using a multi model approach of TCF4 haploinsufficiency aims to address unmet needs in understanding and treating this rare genetic condition. We will focus on the development and formation of specific brain neuronal circuits associated with autism-like behaviors and anxiety, the developmental causes of motor coordination deficits, and the formation of the enteric nervous system—crucial for understanding gastrointestinal symptoms, such as constipation, commonly observed in PTHS patients. Our study take advantege of the unique benefits of a multi model approach to pave the way for novel interventions that address both neurological and gastrointestinal symptoms of Pitt-Hopkins syndrome, ultimately improving quality of life for patients and their families.