title: Forced myofiber regeneration promotes dystrophin gene transfer and improved muscle function despite advanced disease in old dystrophic mice.
abstract: Duchenne muscular dystrophy (DMD) is caused by defects in the dystrophin gene. In young dystrophic mdx mice, immature regenerating myofibers represent the principal substrate for adenovirus vector (AdV)-mediated dystrophin gene transfer. However, in DMD patients immature regenerating myofibers are generally sparse. Such a situation also exists in old mdx mice, which may represent a more realistic model. Therefore, here we have used old mdx mice (of 14- to 17 months of age) to test the hypothesis that one-time administration of a myonecrotic agent can transiently re-establish a population of immature myofibers susceptible to AdV-mediated dystrophin gene transfer. This strategy led to upregulation of the coxsackie/adenovirus attachment receptor by means of induction of regenerating myofibers, significantly augmented AdV-mediated dystrophin gene expression, and enhanced force-generating capacity. In addition, it led to an increased resistance to contraction-induced injury compared with untreated controls. The latter protective effect was positively correlated with the number of dystrophin-expressing myofibers (r=0.83, P<0.05). Accordingly, the risk:benefit ratio associated with the sequential use of forced myofiber regeneration and AdV-mediated dystrophin gene transfer was favorable in old mdx mice despite advanced disease. These findings have implications for the potential applicability of AdV-mediated gene therapy to DMD and other muscle diseases in which immature regenerating myofibers are lacking.
authors.affiliation: Respiratory Division, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada H3A 1A1.
authors.forename: G H
authors.initials: GH
authors.lastname: Guibinga
authors.forename: S
authors.initials: S
authors.lastname: Ebihara
authors.forename: J
authors.initials: J
authors.lastname: Nalbantoglu
authors.forename: P
authors.initials: P
authors.lastname: Holland
authors.forename: G
authors.initials: G
authors.lastname: Karpati
authors.forename: B J
authors.initials: BJ
authors.lastname: Petrof
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016189:Dystrophin / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D004546:Elapid Venoms / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D007150:Immunohistochemistry; D007537:Isometric Contraction; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D009210:Myofibrils / Q000187:drug effects / Q000235:genetics / Q000473:pathology / Q000502:physiology*; D011991:Receptors, Virus / Q000096:biosynthesis / Q000235:genetics; D012038:Regeneration / Q000187:drug effects; D013314:Stress, Mechanical; D019076:Transgenes / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016189:Dystrophin; D004546:Elapid Venoms; D011991:Receptors, Virus; C005082:notexin