The novel use of the CFTR corrector C17 in muscular dystrophy: pharmacological profile and in vivo efficacy

Sarcoglycanopathies are rare forms of severe muscular dystrophies currently without a therapy. Mutations in sarcoglycan (SG) genes cause the reduction or absence of the SG-complex, a tetramer located in the sarcolemma that plays a protective role during muscle contraction. Missense mutations in SGCA, which cause α-sarcoglycanopathy, otherwise known as LGMD2D/R3, lead to folding defective forms of α-SG that are discarded by the cell quality control. Recently, we demonstrated how a small molecule called C17, initially identified as a CFTR corrector, can be re-used to ameliorate the dystrophic phenotype of a mouse model of α-sarcoglycanopathy. Here, we have examined the pharmacological profile of C17 by performing ADME (absorption, distribution, metabolism, and elimination) studies. Our data show that C17 is well-distributed to relevant organs like heart and skeletal muscle, and likely metabolized in the small intestine into hydrophilic and hydrophobic derivatives. Elimination occurs thro...