Small molecules to rescue folding-defective sarcoglycans: in vivo assessment of novel therapeutic strategies

LGMD2D-E , or sarcoglycanopathies, are rare genetic disorders affecting skeletal muscle, confining patients to a wheel-chair and for which no effective therapy is at present available. Sarcoglycanopathies are due to defects on the genes coding for sarcoglycans (SG), four proteins forming a key complex that ensures the integrity of muscle membrane during contraction. Recently, we have deciphered the mechanism responsible for the strong reduction of the SG-complex observed when a mutation produces a folding-defective SG, a condition responsible for most of the sarcoglycanopathy cases. With these information, we designed novel therapeutic strategies and, in the frame of the Telethon exploratory grant 2012, we demonstrated in vitro that is possible to rescue the entire SG-complex by reducing the degradation rate of the defective sarcoglycan by means of compounds either inhibitors of the mutant disposal or protein folding correctors that help the mutant folding process. The efficacy in vitro has been then validated by treating "pathological" cells, i.e., derived from a muscle biopsy of an LGMD2D patient. However, the development of the therapeutic approach deems to verify in vivo the functional recovery of the muscle tissue upon treatment with the compounds. The first aim of this project is the production and characterization of novel mouse models of LGMD2D, because the animal model at present available are unsuitable to our purposes. To verify efficacy and safety of the compounds we can also use a novel model of LGMD2E and the "pathological" cells derived from sarcoglycanopathy patients. We are confident to be able to validate in vivo the proposed pharmacological approach, moving an additional step toward the identification of a cure for those forms of sarcoglycanopathy caused by a folding-defective sarcoglycan.