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Mol Ther. 2014 Apr;22(4):854-61. doi: 10.1038/mt.2013.276. Epub 2013 Dec 9.

Dual masking of specific negative splicing regulatory elements resulted in maximal exon 7 inclusion of SMN2 gene.

Author information

Formerly Department of Clinical Research, Singapore General Hospital, Singapore, Singapore.
A*STAR Institute of High Performance Computing, Singapore, Singapore.
Department of Research, National Skin Centre, Singapore, Singapore.

Erratum in

  • Mol Ther. 2014 Apr;22(4):891. Dwipramono, Zacharias Aloysius [corrected to Pramono, Zacharias Aloysius Dwi].


Spinal muscular atrophy (SMA) is a fatal autosomal recessive disease caused by survival motor neuron (SMN) protein insufficiency due to SMN1 mutations. Boosting SMN2 expression is a potential therapy for SMA. SMN2 has identical coding sequence as SMN1 except for a silent C-to-T transition at the 6th nucleotide of exon 7, converting a splicing enhancer to a silencer motif. Consequently, most SMN2 transcripts lack exon 7. More than ten putative splicing regulatory elements (SREs) were reported to regulate exon 7 splicing. To investigate the relative strength of each negative SRE in inhibiting exon 7 inclusion, antisense oligonucleotides (AONs) were used to mask each element, and the fold increase of full-length SMN transcripts containing exon 7 were compared. The most potent negative SREs are at intron 7 (in descending order): ISS-N1, 3' splice site of exon 8 (ex8 3'ss) and ISS+100. Dual-targeting AONs were subsequently used to mask two nonadjacent SREs simultaneously. Notably, masking of both ISS-N1 and ex8 3'ss induced the highest fold increase of full-length SMN transcripts and proteins. Therefore, efforts should be directed towards the two elements simultaneously for the development of optimal AONs for SMA therapy.

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