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

Abstract

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 through faeces (unmodified and modified C17) and urine (modified forms). Interestingly, we detected a quantifiable amount of C17 in treated muscles 48 h after an acute parenteral administration. This led to design a regimen of chronic treatment with a reduced dosing frequency. The result was the recovery of muscle strength, thanks to the rescue of the SG-complex, despite containing a mutated subunit, at the level of the sarcolemma. Thus, we can conclude that CFTR corrector C17 has a reasonable pharmacological profile and great potential to become a valuable therapeutic option for LGMD2D/R3 and other forms of muscular dystrophy caused by folding defective but potentially functional proteins.