Myotonia therapy through Nav channel slow inactivation
Authors: Chen Pearl , Medepalli Vivek , Dhillon Soneet , Xiong Xeng , Elia Nathaniel , Montalvo Andrea , Rogawski Michael , Feldman Daniel , Lossin Christoph 
Published: November 2023

ObjectiveMyotonia is an acquired or inherited inability to relax skeletal muscle that presents as a stand‐alone disorder or as part of a more complex phenotype in the periodic paralyses, myotonic dystrophy, and paramyotonia congenita. All known forms are channelopathies, precipitated by dysfunction of either the skeletal muscle chloride channel ClC‐1 (gene name: CLCN1) or the voltage‐gated sodium channel Nav1.4 (SCN4A). No FDA‐approved therapy exists, forcing patients to rely on off‐label alternatives such as antiarrhythmic or antiepileptic agents, whose safety and efficacy data in this clinical context are incomplete. Commonly, the therapeutic approach is to subdue muscular excitability by altering fundamental Nav channel characteristics (e.g., shifting the voltage dependence of in‐/activation, prolonging fast inactivation recovery, etc.), which leads to undesirable side effects. We hypothesized that muscular hyperexcitability is better controlled by leaving core Nav channel functionality untouched, while long‐term Nav channel availability is pharmacologically restricted. This is possible through a new group of compounds that favor Nav channel entry into the slow‐inactivated state that, under normal physiological conditions, is only engaged after sustained depolarization. The first marketed agent of this kind, lacosamide (LCM, Vimpat™), has proven beneficial in seizure disorders and an excellent safety profile. Our objective was to explore the benefits of LCM in myotonic hyperexcitability.MethodsFreshly isolated NIH Swiss mouse extensor digitorum longus (EDL) muscle was connected to a force transducer and exposed to the chloride channel blocker 9‐anthracene carboxylic acid (9AC, 100 μM) to induce delayed muscular relaxation and increased force summation typical for myotonia. Whole‐cell voltage clamping (HEK cells) was used to examine whether the observed effect could be mediated through Nav1.4. Cardiac safety profiling employed human stem cell‐derived cardiomyocytes (iCells™, Cellular Dynamics International).Summary of ResultsIntervention with LCM was effective, rescuing near‐control muscle contraction behavior, but it required doses near the clinically recommended upper limit (30–100 μM), which prompted cardiac safety concerns based on our finding that iCell cardiomyocytes stopped beating near 40 μM LCM. Electrophysiological analyses confirmed the possibility that the observed effect is based on modulation of Nav1.5 slow inactivation, more specifically a dramatic hyperpolarizing shift in the voltage dependence.ConclusionSlow inactivation enhancers like LCM constitute an exciting starting point for antimyotonic drug development efforts. Careful analysis of the structure‐activity relationship and derivatization toward elevated potency and improved safety, not only in the heart but also centrally (e.g, by favoring low blood‐brain barrier permeability), will help generate a much needed treatment for myotonic disorders.Support or Funding InformationResearch reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 5R56AR066776. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Insitutes of Health.