Myotonic dystrophy type 1 (DM1) is a genetic disease caused by a triplet CTG expanded repeat in the DMPK gene, which codes for DM protein kinase. The CTG repeat causes an RNA gain-of-function, sequestering muscleblind-like (MBNL) proteins which results in missplicing and pathogenesis. In this study, antisense oligonucleotide (ASO) therapy is employed to block the repeat expansion and reverse RNA toxicity. We used ASO gapmers containing DNA and 2'OMe modified bases for optimal binding affinity and potential RNase H induction. Using DM1 cells to screen ASOs, we have identified a 5-12-4 gapmer that reduces RNA foci in situ. However, immunofluorescence analysis shows no reduction in MBNL protein foci, revealing that RNase H is not effectively cleaving the DNA:RNA hybrids, and that sequestered MBNL protein remains nonfunctional. Therefore, additional nucleotide functionality will need to be further investigated; however our research serves as an important gateway for further ASO therapy in DM1.

Reversal of RNA toxicity in myotonic dystrophy type 1 using antisense oligonucleotides

245th National Meeting (2013)

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