title: Development of multiexon skipping antisense oligonucleotide therapy for Duchenne muscular dystrophy.
abstract: Duchenne muscular dystrophy (DMD) is an incurable, X-linked progressive muscle degenerative disorder that results from the absence of dystrophin protein and leads to premature death in affected individuals due to respiratory and/or cardiac failure typically by age of 30. Very recently the exciting prospect of an effective oligonucleotide therapy has emerged which restores dystrophin protein expression to affected tissues in DMD patients with highly promising data from a series of clinical trials. This therapeutic approach is highly mutation specific and thus is personalised. Therefore DMD has emerged as a model genetic disorder for understanding and overcoming of the challenges of developing personalised genetic medicines. One of the greatest weaknesses of the current oligonucleotide approach is that it is a mutation-specific therapy. To address this limitation, we have recently demonstrated that exons 45-55 skipping therapy has the potential to treat clusters of mutations that cause DMD, which could significantly reduce the number of compounds that would need to be developed in order to successfully treat all DMD patients. Here we discuss and review the latest preclinical work in this area as well as a variety of accompanying issues, including efficacy and potential toxicity of antisense oligonucleotides, prior to human clinical trials.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. tsugu56@gmail.com
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Aoki
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yokota
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D016189:Dystrophin / Q000737:chemistry / Q000235:genetics; D005091:Exons / Q000235:genetics*; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000627:therapeutic use*
chemical_list: D016189:Dystrophin; D016376:Oligonucleotides, Antisense