Pharmacological approaches for the treatment of NF1 bone manifestations – NFbone

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease due to mutations in the NF1 tumor suppressor gene, encoding the RAS-GTPase activating protein neurofibromin, and affecting 1 in 3000 people. NF1 patients can be affected by a variety of symptoms including cutaneous, neurological, orthopedic and malignant manifestations. There is no definitive treatment for NF1. We concentrate on NF1 bone manifestations through analyses of patient samples and a new mouse model of NF1, the Prss56-Nf1 mice, mimicking several aspects of the pathology including bone phenotypes such as scoliosis and pseudarthrosis (absence of bone repair). This project aims to explore new pharmacological approaches to treat these symptoms. We will determine whether MEK inhibitor combined with SHP2 inhibitor can correct (1) spine deformation and (2) pseudarthrosis in the Prss56-Nf1 mouse model, and (3) can ameliorate in vitro differentiation of bone cells from NF1 patients and Prss56-Nf1 mice. Similar treatment has been shown to successfully reduce tumor progression both in animal models and in human. The results of this project will serve as proof of concept that pharmacological treatment can serve to prevent and/or cure dystrophic scoliosis and congenital pseudarthrosis of the tibia in NF1 patients.