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- Title
Development of a single vector system that enhances trans-splicing of SMN2 transcripts.
- Authors
Coady, Tristan H; Baughan, Travis D; Shababi, Monir; Passini, Marco A; Lorson, Christian L
- Abstract
RNA modalities are developing as a powerful means to re-direct pathogenic pre-mRNA splicing events. Improving the efficiency of these molecules in vivo is critical as they move towards clinical applications. Spinal muscular atrophy (SMA) is caused by loss of SMN1. A nearly identical copy gene called SMN2 produces low levels of functional protein due to alternative splicing. We previously reported a trans-splicing RNA (tsRNA) that re-directed SMN2 splicing. Now we show that reducing the competition between endogenous splices sites enhanced the efficiency of trans-splicing. A single vector system was developed that expressed the SMN tsRNA and a splice-site blocking antisense (ASO-tsRNA). The ASO-tsRNA vector significantly elevated SMN levels in primary SMA patient fibroblasts, within the central nervous system of SMA mice and increased SMN-dependent in vitro snRNP assembly. These results demonstrate that the ASO-tsRNA strategy provides insight into the trans-splicing mechanism and a means of significantly enhancing trans-splicing activity in vivo.
- Publication
PloS one, 2008, Vol 3, Issue 10, pe3468
- ISSN
1932-6203
- Publication type
Journal Article
- DOI
10.1371/journal.pone.0003468