Modeling Pitt-Hopkins syndrome and new pathogenetic variants of TCF4 by gene editing: a step forward toward personalized medicine (HOPeFOR)

The advent of new technologies based on the CRISPR/Cas9 technology allows us to generate new models to study rare diseases. In our project we propose to make a significant step forward by reproducing in zebrafish embryos specific mutations of the TCF4 gene, found in patients with Pitt-Hopkins Syndrome, and in three patients with a new TCF4 related disease. Due to the complexity of genetic developmental disorders the use of animal models is still necessary to study the effects of genetic mutations in the entire organism and to test the possible toxicity and/or efficacy of new treatments. Our project takes into consideration the ethical issues related to these aspects, using a small fish as a vertebrate model, mending the experimentation on mammals in later preclinical phases. The zebrafish embryos will carry the same mutation of the patients and will represent their "aquatic avatar" in which to test new treatments suggested by our research. The project will also contribute to study still unknown aspects of the TCF4 related rare diseases such as the identification and validation of new targets to plan new therapeutic strategies. The strength of our proposal is the strong link between basic and applied research. Aware of the great challenge underlying rare disease research, we will produce knowledge and results able to speed up the identification of new therapeutic interventions in the perspective of personalized medicine. This project will also represent an example of a new comparative and integrated Human/fish approach to address and face other rare diseases.