Sarcoglycanopathies, therapeutic approaches based on small molecules

Sarcoglycanopathies are rare autosomal recessive diseases affecting striated muscle, sharing a similar phenotype. The pathology is due to defects in four genes, SGCA, SGCB, SGCD and SGCG coding for α-, β-, δ- and γ-sarcoglycan (SG), respectively. SGs form a key tetramer that, embedded in the major dystrophin associated protein complex, concurs to the structural stability of the sarcolemma during muscle contraction. When a mutation is present in one of the SG-genes, the entire SG-complex disappears or is strongly reduced and a progressive muscle degeneration leads to the development of the disease. Most of the SG-gene defects are missense mutations leading to the production of folding-defective protein, recognized and rapidly removed by the quality control system of the cells. At present, no effective treatment is available for sarcoglycanopathy, however, the knowledge of the pathogenic mechanism allowed us to design a novel pharmacological strategy. Indeed, we proved that by using small molecules able to inhibit some components of the degradative pathway, the mutated SG and the SG-complex can be recovered at the plasma membrane. These results have been collected in cell models and in primary myotubes from an α-sarcoglycanopathy patient. As a second pharmacological approach, we have also tested compounds known as CFTR-correctors supposed acting on the folding process of SGs. The results obtained are extremely promising, as some of these small molecules are effective in recovering the SG-complex in cell models and in myotubes form both α- and β-sarcoglycanopathy patients. Importantly, although containing a defective member, the rescued SG-complex is functional as the strength of the myotube sarcolemma improved, upon treatment with CFTR-correctors. Our lab is currently focusing on the development and characterization of novel mouse and zebrafish models of the disease, suitable for testing effectiveness of the small molecules in vivo. Experiments aiming at understanding the mechanism of action of CFTR-correctors in sarcoglycanopathy are also ongoing.