Pharmacological rescue of misfolded proteins: innovative approaches for the cure of three muscular diseases

Each human body protein, in order to acquire the structure essential for its activity, is subjected to a complex folding mechanism and must pass the careful check up of the cellular quality control system (QCS). Sometimes, minimal protein defects (as a result of mutation) compromise such structure (unfolding or misfolding) inducing QCS to remove the defective polypeptide, divesting cells of the specific protein activity. The subsequent damage provokes the development of a disease called Unfolded Protein Disease (UPD), the paradigm of which is Cystic Fibrosis (CF). Our group is studying three distinct, rare genetic disorders, affecting skeletal and cardiac muscles that we propose to be classified as UPDs. In type 2 Limb Girdle Muscular Dystrophy (LGMD2D), Brody's Disease (BD) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), in fact, mutant proteins are prematurely removed, although they might be at least partially functional, as it happens in CF. Our project proposes an innovative pharmacological approach for the "cure"; of the mutated proteins by using molecules able to either block their degradation or promote their folding. By these treatments, successfully applied in CF research so that several of them are already used in clinical trials, we anticipate to induce a quantitative and qualitative rescue of the mutated proteins, restoring the normal cell function. Thus, the present project is the proof of principle for the development of innovative pharmacological therapies for the cure of rare muscle diseases for which neither classical nor innovative therapies, i.e., gene therapy, are efficacious or applicable.