Myotonia is a heritable muscle cramp disorder that robs patients of their ability to move freely and with purpose. Hands, arms, legs, neck - any willfully movable muscle - may freeze in mid-action, and normal function does not return until the same motion is repeated several times. This not only limits patients in their daily life, but i also exposes them to an incessant risk of falling, leading to mental distress and an overall reduction in the quality of life. Yet, no FDA-approved treatment exists. Instead, therapy relies on secondary actions of drugs never intended for myotonia therapy such as Mexitil, whose primary utility is the rectification of cardiac arrhythmias. Efficacy and safety of these compounds in the context of muscular hyperexcitability are hence unclear. Our long-term goal is to develop safe and effective myotonia therapies. The objective of the work proposed here is to assess the antimyotonic potential of a new therapeutic alley that involves blockade of excess sodium (Na+) channel activity, but leaves housekeeping Na+ channel functionality untouched - an approach already successfully deployed in the antiepileptic agent Vimpat. It is our hypothesis that agents mimicking Vimpat's mechanism of action but with limited access to the brain provide excellent relief from myotonia, based on the rationale that both, muscle and brain, rely on action potential initiation by voltage-gated Na+ channels. Preliminary data in myotonic mice are strongly supportive of our hypothesis. We therefore propose to establish a drug screen and drug development program based on library of compounds mechanistically related to Vimpat.
Our specific aims are designed to assess these compounds'antimyotonic utility at the whole-animal, organ, cellular, and molecular level. Specifically we propose (1) to examine compound performance in animal myotonia using behavioral and electromyographic assays as well as physiological measurements (e.g., force development) in surgically isolated muscle, which will allow us to tailor-synthesize new compounds with heretofore unseen antimyotonic activity, (2) to screen candidate compounds generated in Aim #1 for central and cardiac side effects using behavioral assays and electrocardiographic means followed by HPLC/MS-based pharmacodynamic profiling, and (3) to biophysically characterize those compounds passing Aim #1 and #2, specifically their molecular action on the muscle Na+ channel Nav1.4 and their functional impact on Nav1.4 mutants associated with myotonic disorders. The novelty or our endeavor - to titer Na+ channel activity rather than altering Nav channel function per se - is expected to produce superior myotonia control without occurrence of side effects. This caries particular significance in the context of muscular hyperexcitability: our data are relevant not onl to myotonia, but to therapeutic insufficiencies in general, in particular muscle disorders where the treatment options are limited.
The proposed research seeks to develop safe and effective treatments for myotonia, a muscle cramp disorder that deprives patients of their ability to move freely and with purpose. The study's results will expand the current understanding of muscle pharmacology and potentially open up new and improved therapeutic alleys for suboptimally managed muscle conditions.