Comparative analysis of antisense oligonucleotide sequences targeting exon 53 of the human DMD gene: Implications for future clinical trials

• DOI: 10.1016/j.nmd.2009.10.013
• Publication Date: 2010-01-16T04:16:11Z
• Authors: Linda J. Popplewell; Carl Adkin; Virginia Arechava...; Annemieke Aartsma...; Christa L. de Winter; Steve D. Wilton; Jennifer E. Morgan; Francesco Muntoni; Ian R. Graham; George Dickson
• Keywords: Male; 0301 basic medicine; 570; Base Sequence; Transcription, Genetic; Morpholines; Exon skipping Duchenne muscular dystrophy Antisense oligonucleotides Phosphorodiamidate morpholino oligomer duchenne muscular-dystrophy mdx mouse muscle morpholino oligomers expression mice cells length model; 610; Mice, Transgenic; Exons; Genetic Therapy; Oligonucleotides, Antisense; Morpholinos; Dystrophin; Muscular Dystrophy, Duchenne; Disease Models, Animal; Mice; 03 medical and health sciences; Gene Expression Regulation; Gene Targeting; Mutation; Animals; Humans; Cells, Cultured

Duchenne muscular dystrophy (DMD) is caused by the lack of functional dystrophin protein, most commonly as a result of a range of out-of-frame mutations in the DMD gene. Modulation of pre-mRNA splicing with antisense oligonucleotides (AOs) to restore the reading frame has been demonstrated in vitro and in vivo, such that truncated but functional dystrophin is expressed. AO-induced skipping of exon 51 of the DMD gene, which could treat 13% of DMD patients, has now progressed to clinical trials. We describe here the methodical, cooperative comparison, in vitro (in DMD cells) and in vivo (in a transgenic mouse expressing human dystrophin), of 24 AOs of the phosphorodiamidate morpholino oligomer (PMO) chemistry designed to target exon 53 of the DMD gene, skipping of which could be potentially applicable to 8% of patients. A number of the PMOs tested should be considered worthy of development for clinical trial.