In vivo targeting of the Hippo pathway with peptide for the treatment of Neurofibromatosis type 2 – Pep-it

Neurofibromatosis type 2 (NF2) is a syndrome that predisposes individuals to the development of multiple nerve lesions called schwannomas. NF2 patients have a reduced life expectancy (˜50 years). Surgery, radiotherapy, and some anti-angiogenic treatments show limited benefit and are associated with high morbidity and toxicity. Therefore, the development of new treatments is essential. NF2 is caused by the inactivation of the NF2 gene, leading to the activation of the transcriptional complex formed by the YAP/TAZ and TEAD interaction partners, which stimulates cell proliferation and schwannoma growth. Disrupting the YAP/TAZ-TEAD complex represents a promising strategy for treating schwannomas. This can be achieved through peptides (CPPs) that combine a cell-penetrating sequence with a sequence that disrupts the YAP/TAZ-TEAD complex. Our group has validated such a peptide, which dissociates YAP/TAZ-TEAD in vitro and inhibits the proliferation of NF2 cell models with an efficacy close to the one observed for small molecules inhibitors that are already being clinically evaluated. However, its ability to inhibit schwannoma development in vivo in an animal model must be demonstrated to make it a credible candidate for future clinical development. We have established a consortium of four teams specializing in peptide chemistry, protein structure, and NF2 cell and animal models. We propose to combine our expertise to evaluate the stability of the peptide once injected into animals, modify the peptide to stabilize it if necessary, and test its effectiveness in vivo on human schwannoma xenografts in mice. In addition, we will create new cellular models of NF2 from surgical biopsies obtained in the context of a collaboration with the Tissue Bank of Hopital Cochin and the Neuropathology et de Neurosurgery departments of the Hopital Pitié Salpêtrière in Paris, in order to produce a more comprehensive evaluation of the efficacy of the peptides.