Periodic paralysis (PP) is a rare, dominantly inherited myopathy presenting with recurrent episodes of transient weakness lasting hours that are initially reversible but then after decades slowly progresses to permanent proximal weakness with possible loss of ambulation. PP is caused by missense mutations of ion channel genes, resulting in gain-of-function defects (SCN4A for hyperkalemic PP) or in leaky channels (CACNA1S or SCN4A for hypokalemic PP). Interventions to maintain serum K+ (4.0 to 5.0 mM range) or to open K channels (KCNQ agonists) are partially effective for management of episodic attacks, but no treatment is available to slow or prevent permanent weakness.
We sought a durable intervention for both episodic weakness and late myopathy by using CRISPR/Cas-9 nuclease to selectively ablate the mutant allele in mouse models of PP. Disruption of mutant alleles (indel formation in SCN4A p.M1592V, p.R669H; CACNA1S p.R528H) was achieved with 50% to 70% efficiency, without detectable effects on the WT allele. This level of gene editing was sufficient to restore baseline contractility and to prevent K-challenge induced loss of force in PP susceptible muscle. This pre-clinical study in murine PP established feasibility for mutant allele-specific ablation by CRISPR/Cas-9, removes susceptibility to episodic attacks of weakness, and may also prevent or attenuate late onset permanent myopathy.