title: Comparative analysis of antisense oligonucleotide sequences targeting exon 53 of the human DMD gene: Implications for future clinical trials.
abstract: 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.
authors.affiliation: School of Biological Sciences, Royal Holloway - University of London, Egham, Surrey TW20 0EX, United Kingdom.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Popplewell
authors.forename: Carl
authors.initials: C
authors.lastname: Adkin
authors.forename: Virginia
authors.initials: V
authors.lastname: Arechavala-Gomeza
authors.forename: Annemieke
authors.initials: A
authors.lastname: Aartsma-Rus
authors.forename: Christa L
authors.initials: CL
authors.lastname: de Winter
authors.forename: Steve D
authors.initials: SD
authors.lastname: Wilton
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Morgan
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Ian R
authors.initials: IR
authors.lastname: Graham
authors.forename: George
authors.initials: G
authors.lastname: Dickson
mesh_terms: D000818:Animals; D001483:Base Sequence / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016189:Dystrophin / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D005091:Exons / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D060172:Morpholinos; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: C484258:DMD protein, human; D016189:Dystrophin; D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense