PRECLINICAL TRIALS WITH PROMPT-TO-USE DRUGS TARGETING INFLAMMATORY/ISCHEMIC PATHWAYS IN ANIMAL MODELS OF DUCHENNE MUSCULAR DYSTROPHY: FUNCTIONAL, HISTOLOGICAL, BIOPHYSICAL AND BIOCHEMICAL EVALUATION OF THERAPEUTIC EFFECTIVENESS

Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy. Patients show a genetic defect, which leads to absence of cytoskeleton protein dystrophin, important in determining muscle contraction. These patients become wheelchair-bound at the age of 10-12 and succumb to respiratory failure in their late teens-early twenties due to involvement of diaphragm and other respiratory muscles. The possibility to insert the lack gene in these patients may represent a hope for solving the pathology, but until now this possibility is complicated by reject of extraneous tissues. Thus the only way to ameliorate the quality of life in these patients is conventional drug therapy. At this aim we plan to perform pre-clinical studies by testing different prompt-to-use drugs able to counteract cellular alteration responsible for the progression of disease. The study will be performed on the mdx mouse model, having the same genetic defect of DMD patients, undergoing a chronic exercise protocol at the aim to worsen the dystrophic phenotype and to make it more similar to the human counterpart. Drugs have been chosen on the basis of mechanisms of action and pathway involved and will be mostly anti-inflammatory, immunosuppressive and antiischemic agents. In fact dystrophic muscles are characterized by a chronic inflammatory state, which may account for both symptoms and disease progression. At the end of the in vivo chronic treatments, drug efficacy will be estimated as the ability to preserve in vivo muscle strength (Phase1). Compounds effective on this parameter will go to phase 2, aimed at evaluating the efficacy of in vivo treatment on specific cellular parameters, indexes of proper muscle function, as well as on muscle histology. Compound effective in phase1 and 2 (after 2 years of project) will be proposed to collaborating clinical center for clinical trials in Duchenne patients.