Human dystrophin expression corrects the myopathic phenotype in transgenic mdx mice.
Duchenne and the less severe Becker form of muscular dystrophy (DMD,BMD) result from genetic deficiency in the level and/or activity of the protein dystrophin. The recent availability of cDNA based minigenes encoding recombinant dystrophin polypeptides has raised the possibility of somatic gene transfer as a therapeutic approach to treat dystrophin deficiency. In this respect, the mdx mouse provides a useful model of DMD exhibiting features characteristic of both the early myopathic and later fibrotic phases of the human disease. Using a mutated human cDNA, compatible in size with virus-based somatic gene transfer vectors, the pathophysiological consequences of restoring dystrophin expression have been examined in transgenic mdx mice. Transgene expression was correlated with a marked reduction of the skeletal myofibre necrosis and regeneration which is a major feature of the dystrophin-deficient phenotype in young mdx mice. The cDNA construct which is based on a very mild BMD phenotype thus encodes a highly functional dystrophin molecule whose reduced size renders it an attractive candidate for development as a therapeutic gene transfer reagent.
Wells
D J
DJ
Department of Veterinary Basic Sciences, Royal Veterinary College, London, UK.
Wells
K E
KE
Walsh
F S
FS
Davies
K E
KE
Goldspink
G
G
Love
D R
DR
Chan-Thomas
P
P
Dunckley
M G
MG
Piper
T
T
Dickson
G
G
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D003001:Cloning, Molecular; D003402:Creatine Kinase / Q000097:blood; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D016189:Dystrophin / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D010641:Phenotype; D010957:Plasmids; D016133:Polymerase Chain Reaction / Q000379:methods
D016189:Dystrophin; D004247:DNA; D003402:Creatine Kinase