Novel therapies for inherited muscle diseases

DESCRIPTION provided by applicant The pursuit of novel therapies informed by the astounding advances in biomedical science of the past half century has been fruitful for many disorders However inherited muscle diseases such as muscular dystrophy remain stubbornly resistant to sophisticated molecular approaches to therapy A few therapies are finally edging towards approval but it has become clear that the optimal care of affected patients will arise from a combination of therapies as in many other chronic complex diseases This project proposes a creative approach to the identification and development of novel therapeutic compounds for MEGF myopathy a rare inherited muscle disease In this Phase I STTR Medosome Biotec and its research partners at the University of Florida and Tufts Medical Center will use a two step screening process An in vitro screen will make use of cell lines that express mutant forms of MEGF cell proliferation adhesion and migration patterns will be the outcome measures An in vivo screen will focus on Drosophila that are deficient in drpr the fly gene that is homologous to human MEGF This will be accomplished through the following Specific Aims To screen drug libraries for efficacy in rescuing the cellular defects found in MEGF myopathy As MEGF deficiency impairs myoblast proliferation the outcome measure to be used will be augmentation of this critical process along with measures of cell adhesion and migration and To screen the most promising drugs from Aim in drpr knockout Drosophila The outcome measures to be used will include lifespan mobility and histological analyses Drpr deficient flies have been documented to have an easily quantified motor phenotype characterized by locomotor defects on negative geotaxis assays These flies have also been described to have muscle histological abnormalities Thus both levels of screening will have easily quantifiable outcome measures The most promising of these compounds that emerge from the screening process in this Phase I will be studied further in a Phase II project involving mammalian models with an eye towards human clinical trials in preparation for commercialization Preliminary studies conducted in the laboratories at the University of Florida and Tufts Medical Center indicate that MEGF and Drpr deficiency produce clear measurable phenotypes in cell culture and Drosophila respectively enabling the team to construct promising assays in both systems for the development of novel therapies for the human disease Medosome Biotec and its research partners are confident that this approach to drug development has the potential to be applied to a broader array of inherited muscle diseases as cell based and Drosophila models currently exist or may be easily developed for a number of these muscle diseases The potential market for drugs developed in this manner could encompass a significant proportion of individuals affected by inherited muscle diseases such as muscular dystrophy Such therapies are likely to have international appeal as these rare diseases are becoming increasingly recognized around the world PUBLIC HEALTH RELEVANCE The proposed project will develop a creative approach to screen potential drug therapies for a rare muscle disease MEGF myopathy Cell based assays and then Drosophila based assays will be used to screen libraries of compounds The goals of the project will be to identify plausible therapeutic candidates and to validate this approach to high throughput screening of drug libraries