Journal
GENE THERAPY
Volume 16, Issue 2, Pages 211-217Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2008.150
Keywords
dystrophia myotonica type 1 (DM1); trans-splicing; RNA correction; dystrophia myotonica protein kinase gene (DMPK)
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Funding
- Singapore Millennium Foundation
- National Medical Research Council of Singapore [NMRC/0607/2001, NMRC/1098/2006]
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Dystrophia myotonica type 1 (DM1), the most common muscular dystrophy in adults, results from expansion of a CTG repeat in the 30-untranslated region of the dystrophia myotonica protein kinase gene (DMPK). Correction of the mutant DMPK transcript is a potential therapeutic strategy in DM1. We investigated the efficacy of artificial trans-splicing molecules (ATMs) to target and correct DMPK transcripts. ATMs designed to target intron 14 of DMPK pre-mRNA transcripts were tested for their ability to trans-splice the transcripts of a DMPK mini-gene construct and the endogenous DMPK transcripts of human myosarcoma cells (CCL-136). On agarose gel electrophoresis analysis, six of eight ATMs showed trans-splicing efficacy when applied to DMPK mini-gene construct transcripts, of which three were able to trans-splice endogenous DMPK pre-mRNA transcripts in myosarcoma cells, with trans-splicing efficiency ranging from 1.81 to 7.41%. These findings confirm that artificial trans-splicing can repair DMPK pre-mRNA and provide proof-of-principle evidence for this approach as potential therapeutic strategy for DM1.
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