Correction of CIC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy

In myotonic dystrophy (dystrophia myotonica [DM]), an increase in the excitability of skeletal muscle leads to as myotonia, is associated with abnormal alternative splicing of the muscle-specific chloride channel (CIC-1) and reduced conductance of chloride ions in the sarcolemma. However, the mechanistic basis of the chloride channelopathy and its relationship to the development of myotonia are uncertain. Here we show that a morpholino antisense oligonucleotide (AON) targeting the 3 ' splice site of CIC-1 exon 7a reversed the defect of CIC-1 alternative splicing in 2 mouse models of DM. By repressing the inclusion of this exon, the AON restored the full-length reading frame in CIC-1 mRNA, upregulated the level of CIC-1 mRNA, increased the expression of CIC-1 protein in the surface membrane, normalized muscle CIC-1 current density and deactivation kinetics, and eliminated myotonic discharges. These observations indicate that the myotonia and chloride channelopathy observed in DM both result from abnormal alternative splicing of CIC-1 and that antisense-induced exon skipping offers a powerful method for correcting alternative splicing defects in DM.