Towards a therapeutic inhibition of dystrophin exon 23 splicing in mdx mouse muscle induced by antisense oligoribonucleotides (splicomers): target sequence optimisation using oligonucleotide arrays

The Journal of Gene Medicine
Ian R GrahamGeorge Dickson

Abstract

The activity of synthetic antisense oligonucleotides (splicomers) designed to block pre-mRNA splicing at specific exons has been demonstrated in a number of model systems, including constitutively spliced exons in mouse dystrophin RNA. Splicomer reagents directed to Duchenne muscular dystrophy (DMD) RNAs might thus circumvent nonsense or frame-shifting mutations, leading to therapeutic expression of partially functional dystrophin, as occurs in the milder, allelic (Becker) form of the disease (BMD). Functional and hybridisation array screens have been used to select optimised splicomers directed to exon 23 of dystrophin mRNA which carries a nonsense mutation in the mdx mouse. Splicomers were transfected into cultured primary muscle cells, and dystrophin mRNA assessed for exon exclusion. Splicomers were also administered to the muscles of mdx mice. Oligonucleotide array analyses with dystrophin pre-mRNA probes revealed strong and highly specific hybridisation patterns spanning the exon 23/intron 23 boundary, indicating an open secondary structure conformation in this region of the RNA. Functional screening of splicomer arrays by direct analysis of exon 23 RNA splicing in mdx muscle cultures identified a subset of biologically ac...Continue Reading

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Citations

Jan 15, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Linda J PopplewellIan R Graham
Mar 19, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Chalermchai MitrpantSteve D Wilton
Dec 14, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·P L HardingS D Wilton
Jun 1, 2012·Human Gene Therapy·Helen FosterGeorge Dickson
Mar 26, 2013·Human Gene Therapy·Taeyoung Koo, Matthew J Wood
May 31, 2008·Human Molecular Genetics·Mohammad M Ghahramani SenoGeorge Dickson
Jun 17, 2009·Expert Opinion on Biological Therapy·Capucine TrolletGeorge Dickson
Nov 14, 2008·The Journal of Gene Medicine·Chalermchai MitrpantSteve D Wilton
Jun 21, 2011·Artificial DNA, PNA & XNA·Camilla Brolin, Takehiko Shiraishi
Oct 27, 2006·Gene Therapy·K FosterJ G Dickson

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