Evaluation of in vivo efficacy duration and oral bioavailability of corrector C17, a drug candidate for LGMDR3.

Limb-girdle muscular dystrophy type R3 (LGMDR3) is a severe inherited myopathy caused by mutations in the SGCA gene, which may lead to misfolding and premature degradation of α-sarcoglycan (α-SG) and destabilization of the SG complex at the sarcolemma. Recent studies have evidenced the therapeutic potential of C17, a small molecule shown to promote proper folding of mutated α-SG and the traffic toward the membrane of the SG complex. In this work I have been involved in evaluating both the duration of the therapeutic effect and the pharmacokinetic profile of C17 following oral administration in a preclinical mouse model of LGMDR3. We first assessed the persistence of therapeutic efficacy after chronic administration of C17 by daily intraperitoneal (i.p.) injection for five weeks of the LGMDR3 mouse model. To determine how long the therapeutic benefits persisted after treatment cessation, we performed in vivo measurements of muscle force at 1, 3, and 7 days post-treatment. Additionally, we investigated downstream effects on muscle structure and α-SG localization at the sarcolemma by performing histological and immunofluorescence analyses of the Tibialis Anterior muscle. To explore more clinically feasible and patient-friendly delivery routes, we studied the pharmacokinetics of C17 following a single oral administration in mice. Plasma concentrations of C17 were measured at several time points using high-performance liquid chromatography (HPLC), providing information on absorption and bioavailability via the oral route. Together, these experiments contribute to understanding both the duration of therapeutic effects and the delivery potential of C17, supporting its further development as a promising candidate drug for sarcoglycanopathies.