title: Systemic Delivery of Morpholinos to Skip Multiple Exons in a Dog Model of Duchenne Muscular Dystrophy.
abstract: Exon-skipping therapy is an emerging approach that uses synthetic DNA-like molecules called antisense oligonucleotides (AONs) to splice out frame-disrupting parts of mRNA, restore the reading frame, and produce truncated yet functional proteins. Multiple exon skipping utilizing a cocktail of AONs can theoretically treat 80-90% of patients with Duchenne muscular dystrophy (DMD). The success of multiple exon skipping by the systemic delivery of a cocktail of AONs called phosphorodiamidate morpholino oligomers (PMOs) in a DMD dog model has made a significant impact on the development of therapeutics for DMD, leading to clinical trials of PMO-based drugs. Here, we describe the systemic delivery of a cocktail of PMOs to skip multiple exons in dystrophic dogs and the evaluation of the efficacies and toxicity in vivo.
authors.affiliation: Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton, AB, Canada.
authors.forename: Rika
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton, AB, Canada.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Echigoya
authors.affiliation: Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton, AB, Canada.
authors.forename: Oana
authors.initials: O
authors.lastname: Caluseriu
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton, AB, Canada. toshifum@ualberta.ca.|The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Science Endowed Research Chair, Edmonton, AB, Canada. toshifum@ualberta.ca.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yokota
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D005786:Gene Expression Regulation; D023061:Gene Order; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D060172:Morpholinos / Q000008:administration & dosage / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010641:Phenotype
chemical_list: D016189:Dystrophin; D060172:Morpholinos; D016376:Oligonucleotides, Antisense
keywords: Canine X-linked muscular dystrophy (CXMD); Duchenne/Becker muscular dystrophies (DMD/BMD); Dystrophic dogs; Dystrophin; Exon skipping; Morpholinos (phosphorodiamidate morpholino oligomers)