Stabilization of expanded (CTG).(CAG) repeats by antisense oligonucleotides

Abstract

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the gene DMPK. The expansion is highly unstable in somatic cells, a feature that may contribute to disease progression. The RNA expressed from the mutant allele exerts a toxic gain of function, due to the presence of an expanded CUG repeat (CUG exp). This RNA dominant mechanism is amenable to therapeutic intervention with antisense oligonucleotides (ASOs). For example, CAG-repeat ASOs that bind CUG exp RNA are beneficial in DM1 models by altering the protein interactions or metabolism of the toxic RNA. Because CUG exp RNA has been shown to aggravate instability of expanded CTG repeats, we studied whether CAG-repeat ASOs may also affect this aspect of DM1. In human cells the instability of (CTG) 800 was suppressed by addition of CAG-repeat ASOs to the culture media. In mice that carry a DMPK transgene the somatic instability of (CTG) 800 was suppressed by direct injection of CAG-repeat ASOs into muscle tissue. These results raise the possibility that early intervention with ASOs to reduce RNA or protein toxicity may have the additional benefit of stabilizing CTG:CAG repeats at subpathogenic lengths. © The American Society of Gene & Cell Therapy.