Toward precision medicine in myotonic syndromes

The large number of physiological processes regulated by voltage-gated sodium channels (Na v) and their role in many diseases make these channels highly interesting as targets for new drugs. Current research in the pharmaceutical industry mainly focuses on identifying sodium channel blockers that may have therapeutic application in widespread pathological conditions, including epilepsy, cardiac arrhythmias, and chronic pain. There is much less research regarding sodium channel drugs relevant to rare human genetic diseases, including nondystrophic myotonias (NDM). Myotonia is a skeletal muscle condition characterized by over-excitability of sarcolemma, resulting in delayed relaxation after contraction and muscle stiffness. Inherited NDM are caused by gain-of-function mutations in hNa v 1.4 sodium channel or loss-of-function of hClC-1 chloride channel. Severity of symptoms ranges from mild to severe, the later condition affecting daily movements and deteriorating quality of life. More recently, life-threatening events have been reported in neonates suffering from severe episodic neonatal laryngospasms caused by Na v 1.4 mutations. After two decades of off-label use in NDM, mexiletine was recently appointed as an orphan drug in myotonic syndromes. By blocking skeletal muscle sodium channels, mexiletine can counteract sarcolemma over-excitability and alleviate symptoms, whatever myotonia is caused by sodium or chloride channel mutations. However, some myotonic patients cannot take mexiletine because of side effects or contraindications, while others, estimated to be nearly 20%, do not obtain satisfactory response to mexiletine [1]. Alternative drugs to mexiletine are definitely needed. We are currently pursuing various strategies to identify new promising therapies for NDM. We combined electrophysiology and molecular modeling to study Na v blockers, and we recently developed a pharmacologically-induced model of myotonia in the rat. First, we compared a number of marketed sodium channel blockers to mexiletine [2]. We found that the anti-myotonic activity of drugs in vivo was closely parallel to inhibition in vitro of sodium currents elicited by high-frequency voltage-clamp protocols in mammalian cells transfected with hNa v 1.4 cDNA. Riluzole, currently indicated for amyotrophic lateral sclerosis, appeared as a very potent antimyotonic drug in the rat model and a human pilot study has been recently launched for NDM. Second, for many years we have performed a series of structural-activity relationship studies to define the molecular interactions of mexiletine and its relative, tocainide, with Na v 1.4 channels [3, 4]. These studies provided new insights into the relative role of pharmacophores for binding to crucial amino acid residues in Na v and suggest …