Molecular pathways in Schwannomatosis: exploiting in vitro models for the identification of new therapeutic targets

Neurofibromatoses are a group of neurologic diseases characterized by a genetic predisposition to formation of peripheral nerve tumors. Neurofibromatosis type 3, also called Schwannomatosis (SCH), is the rarest and less known form, whose genetic bases have been started to be elucidated only in the last ten years. Beside typical somatic truncating mutations of the NF2 gene (coding for the protein merlin) that are found in schwannomas, germline mutations in at least two distinct genes, SMARCB1 and LZTR1, have been recently associated with SCH. However, some patients still lack a genetic diagnosis and the complete knowledge of the pathogenic mechanisms involved in SCH-related tumorigenesis is still lacking, supporting the hypothesis that other loci close to the NF2 gene may participate in schwannoma pathogenesis. Likewise, the cellular and biological mechanisms through which either SMARCB1 or LZTR1 mutations cause different phenotypes remain elusive. Importantly, although the clinical features of SCH are partially known, the main goal in this disorder is the discovery of drugs that can inhibit/reduce tumor development and manage pain associated with tumor growth. The excruciatingly intense pain, indeed, is the prevalent symptom of SCH, for which a reliable therapy is currently unavailable. In this project we propose to develop and characterize different genetic models of SCH and to integrate the information obtained in order to identify novel therapeutic targets. To this end, we plan to use in vitro cell lines reproducing the SCH 4-hit/3-step model of gene inactivation, human primary Schwann cell cultures from SCH patients, and in vivo analysis of SCH molecular pathways in C. Elegans and Zebrafish mutants. Thereby, the main objective of this proposal is the identification of genes, pathways and molecular targets critical for SCH pathogenesis, diagnosis and treatment. In addition, the development of in vitro or simple animal models for this disease will greatly help the pre-clinical drug-screening of therapeutic agents for the treatment of SCH. Wide exome sequencing approach will be applied to identify other genes associated with NF2, SMARCB1 and/or LZTR1, and potentially involved in SCH pathogenesis. We are confident that our in vitro/in vivo models will help to clarify the molecular bases of this disorder. Our proposal is a basic, pre-clinical and pre-competitive research in the field of neuroscience, neurogenetic and neuropharmacology. In particular, the project gather three leading groups in the field of SCH, peripheral nervous system and Schwann investigations. In this light, the project represents a strategy towards the identification of new molecular targets that are critical for SCH pathogenesis, treatment and management.