title: High-level dystrophin expression after adenovirus-mediated dystrophin minigene transfer to skeletal muscle of dystrophic dogs: prolongation of expression with immunosuppression.
abstract: Replication-deficient adenovirus vectors (AdV) have been successfully used to transfer a truncated human dystrophin cDNA to skeletal muscle of dystrophin-deficient mdx mice. A dystrophin-deficient golden retriever dog model (GRMD) has been identified, which, unlike the mouse model, leads to a clinicopathological phenotype similar to that of Duchenne muscular dystrophy (DMD). We show for the first time that high-level dystrophin expression in skeletal muscle of GRMD dogs can be achieved by AdV-mediated gene transfer. However, a humoral and cellular immune response of the host against antigens of viral and transgene origin (similar to that occurring in mdx mice after AdV-mediated dystrophin gene transfer) leads to a decline of dystrophin expression over a 2-month period. Immunosuppression by cyclosporin significantly prolonged transgene expression. The GRMD model may help to solve the open questions pertaining to dystrophin gene transfer such as systemic delivery and improvement of muscle function before human trials for gene replacement therapy in DMD may be considered.
authors.affiliation: Division of Veterinary and Biomedical Sciences, Murdoch University, Western Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Howell
authors.forename: H
authors.initials: H
authors.lastname: Lochmüller
authors.forename: A
authors.initials: A
authors.lastname: O'Hara
authors.forename: S
authors.initials: S
authors.lastname: Fletcher
authors.forename: B A
authors.initials: BA
authors.lastname: Kakulas
authors.forename: B
authors.initials: B
authors.lastname: Massie
authors.forename: J
authors.initials: J
authors.lastname: Nalbantoglu
authors.forename: G
authors.initials: G
authors.lastname: Karpati
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D016189:Dystrophin / Q000096:biosynthesis / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009137:Muscular Dystrophy, Animal / Q000235:genetics*
chemical_list: D016189:Dystrophin