Journal article
Comparative analysis of antisense oligonucleotide sequences for targeted skipping of Exon 51 during dystrophin Pre-mRNA splicing in human muscle
Human Gene Therapy, Vol.18(9), pp.798-810
2007
Abstract
Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in the absence of functional protein. In the majority of cases these are out-of-frame deletions that disrupt the reading frame. Several attempts have been made to restore the dystrophin mRNA reading frame by modulation of pre-mRNA splicing with antisense oligonucleotides (AOs), demonstrating success in cultured cells, muscle explants, and animal models. We are preparing for a phase I/IIa clinical trial aimed at assessing the safety and effect of locally administered AOs designed to inhibit inclusion of exon 51 into the mature mRNA by the splicing machinery, a process known as exon skipping. Here, we describe a series of systematic experiments to validate the sequence and chemistry of the exon 51 AO reagent selected to go forward into the clinical trial planned in the United Kingdom. Eight specific AO sequences targeting exon 51 were tested in two different chemical forms and in three different preclinical models: cultured human muscle cells and explants (wild type and DMD), and local in vivo administration in transgenic mice harboring the entire human DMD locus. Data have been validated independently in the different model systems used, and the studies describe a rational collaborative path for the preclinical selection of AOs for evaluation in future clinical trials.
Details
- Title
- Comparative analysis of antisense oligonucleotide sequences for targeted skipping of Exon 51 during dystrophin Pre-mRNA splicing in human muscle
- Authors/Creators
- V. Arechavala-Gomeza (Author/Creator) - Imperial College LondonI.R. Graham (Author/Creator)L.J. Popplewell (Author/Creator)A.M. Adams (Author/Creator) - Centre for Neuromuscular and Neurological DisordersA. Aartsma-Rus (Author/Creator)M. Kinali (Author/Creator)J.E. Morgan (Author/Creator)J.C. van Deutekom (Author/Creator)S.D. Wilton (Author/Creator) - Centre for Neuromuscular and Neurological DisordersG. Dickson (Author/Creator)F. Muntoni (Author/Creator)
- Publication Details
- Human Gene Therapy, Vol.18(9), pp.798-810
- Publisher
- Mary Ann Liebert Inc.
- Identifiers
- 991005543992707891
- Copyright
- 2007 Mary Ann Liebert Inc.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.255 Musculoskeletal Disorders
- 1.255.628 Duchenne Muscular Dystrophy
- Web Of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental
- ESI research areas
- Molecular Biology & Genetics