CFTR correctors for the treatment of type 2D Limb Girdle Muscular Dystrophy

Limb Girdle Muscular Dystrophy type 2D (LGMD2D) is a rare autosomal-recessive disease affecting striated muscle, due to mutation of the gene coding for α-sarcoglycan. More than 50 different missense mutations are known to impair folding and trafficking of the protein that is recognized by the endoplasmic reticulum quality control and prematurely degraded by the ubiquitin proteasome system. This leads to the secondary deficiency of three α-sarcoglycan partners, β-, γ- and δ-sarcoglycan, and the disruption of a key complex that assures sarcolemma stability during muscle contraction. The consequent loss of function, even when the folding-defective protein retains its function, is responsible for muscle wasting and the development of a severe progressive form of dystrophy. Disease severity is strictly related to the residual level of sarcoglycans in the sarcolemma, with the most severe forms characterized by the almost complete loss of the proteins. Protein misfolding is implicated in the pathogenesis and progression of many diseases, among which cystic fibrosis is the most studied. In cystic fibrosis the most frequently reported mutation is the deletion F508 in the CFTR (cystic fibrosis transmembrane conductance regulator) protein which causes misfolding and degradation of the chloride channel. CFTR correctors are a group of small molecules developed for their ability to recover on the cell surface the mutated protein, restoring at least partially its function. These molecules are supposed to act as pharmacological chaperones, promoting the correct folding of the mutated protein, or as proteostasis regulators, modulating the protein quality control system of the cell. Here we show that by using correctors known to rescue ΔF508-CFTR trafficking it is possible to recover different α-sarcoglycan mutants that re-localize at the plasma membrane. Remarkably, when this pharmacological approach is applied in primary myogenic cells from a LGMD2D patient, the sarcoglycan complex is rescued at the proper cellular site. Although the mechanism of action of CFTR correctors on α-sarcoglycans is still unknown and needs to be clarified, these data represent the proof of principle that a “protein repair strategy” can be developed to treat LGMD2D utilizing well-known and available small molecules correcting mutant folding.