Non-toxic ubiquitous over-expression of utrophin in the mdx mouse.
Duchenne muscular dystrophy (DMD) is an inherited, severe muscle wasting disease caused by the loss of the cytoskeletal protein, dystrophin. Patients usually die in their late teens or early twenties of cardiac or respiratory failure. We have previously demonstrated that the dystrophin related protein, utrophin is able to compensate for the loss of dystrophin in the mdx mouse, the mouse model of the disease. Expression of a utrophin transgene under the control of an HSA promoter results in localization of utrophin to the sarcolemma and prevents the muscle pathology. Here we show that the over-expression of full-length utrophin in a broad range of tissues is not detrimental in the mdx mouse. These findings have important implications for the feasibility of the up-regulation of utrophin in therapy for DMD since they suggest that tissue specific up-regulation may not be necessary.
Fisher
R
R
MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK.
Tinsley
J M
JM
Phelps
S R
SR
Squire
S E
SE
Townsend
E R
ER
Martin
J E
JE
Davies
K E
KE
D000375:Aging; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D003404:Creatinine / Q000652:urine; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005240:Feasibility Studies; D015870:Gene Expression; D015316:Genetic Therapy; D006720:Homozygote; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D014018:Tissue Distribution / Q000235:genetics; D019076:Transgenes; D015854:Up-Regulation / Q000235:genetics; D049411:Utrophin
D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C483600:Utrn protein, mouse; D049411:Utrophin; D003404:Creatinine