Redesign of trans-splicing molecules for the correction of dystrophia myotonica type 1 toxic RNA transcripts

Dystrophia myotonica (DM1), one of the most common forms of muscular dystrophy, is caused by a repeated trinucleotide expansion in the DMPK gene. This mutation results in the accumulation of toxic cellular RNA transcripts. Spliceosome-mediated RNA trans-splicing (SMaRT) technology is a form of gene therapy that possesses the potential to correct these toxic RNA transcripts and thus cure the disease. Despite its promise, prior research applications of SMaRT technology to DM1 have been hampered by poor efficiency and have not been validated in a relevant model of the disease. In order to improve the efficiency of trans-splicing, this study examined the use of novel SMaRT molecules containing altered binding domains. These SMaRT molecules were tested in a clinically relevant cell model of DM1 and their corrective ability compared with that of a standard SMaRT molecule. The results were quantified by RT-PCR. The outcome of this study indicated the need to utilize more specific methods for measuring efficiency and for understanding the specific interactions of SMaRT molecules with target transcripts