Induced dystrophin exon skipping in human muscle explants.
Antisense oligonucleotide (AO) manipulation of pre-mRNA splicing of the dystrophin gene is showing promise in overcoming Duchenne muscular dystrophy (DMD)-causing mutations. To date, this approach has been limited to studies using animal models or cultured human muscle cells, and evidence that AOs can induce exon skipping in human muscle has yet to be shown. In this study, we used different AO analogues to induce exon skipping in muscle explants derived from normal and DMD human tissue. We propose that inducing exon skipping in human muscle explants is closer to in vivo conditions than cells in monolayer cultures, and may minimize the numbers of participants in Phase I clinical studies to demonstrate proof of principle of exon skipping in human muscle.
McClorey
G
G
Experimental Molecular Medicine Group, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA 6009, Australia.
Fall
A M
AM
Moulton
H M
HM
Iversen
P L
PL
Rasko
J E
JE
Ryan
M
M
Fletcher
S
S
Wilton
S D
SD
D000818:Animals; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D016189:Dystrophin / Q000096:biosynthesis / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D015316:Genetic Therapy / Q000379:methods / Q000639:trends; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics
D016189:Dystrophin; D016376:Oligonucleotides, Antisense; D012322:RNA Precursors