[P3-143] Myotonia therapy through Nav channel slow inactivation
Myotonia is an inherited, temporary inability to relax skeletal muscle due to dysfunction of either the skeletal muscle chloride channel ClC-1 (gene: CLCN1) or the voltage-gated sodium channel Nav1.4 (SCN4A). No FDA-approved therapy exists, forcing patients to rely on off-label alternatives (e.g., mexiletine), which alter fundamental Nav channel behavior that results in undesirable side effects. We hypothesized that improved muscular hyperexcitability control may be achieved by leaving core Nav channel functionality untouched, while Nav channel availability is pharmacologically reduced. To that end, we tested Nav channel slow inactivation enhancers (SIEs) on murine models, where myotonia was induced either chemically or present through genetic alteration of the mClcn1 gene. The extensor digitorum longus muscle was excised and connected to a force transducer for tension measurements following electrical stimulation. Exposure to the ClC-1 blocker 9-anthracene carboxylic acid reliably induced myotonia as measured by the relaxation time following stimulus termination. Addition of SIEs (lacosamide and four derivatives, ranolazine, zonisamide, licarbazepine) rescued myotonic relaxation delay in both chemical and genetic myotonia. To assess cardiotoxicity, we used Fura-2 based microplate Ca2+ imaging of iCell™ cardiomyocytes. Combined, our analyses identified ranolazine as an excellent antimyotonic therapy candidate, owing to its ability to effectively attenuate myotonia at sub-cardiotoxic concentrations. Other probes had antimyotonic properties were promising, but cardiotoxicity concerns, so far, limit their utility in therapy. We conclude that further derivatization is necessary to identify clear structure-activity relationships that combine high antimyotonic benefit with cardiac tolerability.