title: AAV-microdystrophin therapy improves cardiac performance in aged female mdx mice.
abstract: Dystrophin deficiency leads to lethal dilated Duchenne cardiomyopathy. A promising therapy is to deliver a highly abbreviated microdystrophin gene to the heart using adeno-associated virus (AAV). Microdystrophin has been shown to mitigate dystrophin-deficient skeletal muscle disease. However, it is not clear whether microdystrophin is equally effective in treating Duchenne cardiomyopathy. To evaluate microdystrophin therapy in the heart, we injected 5 × 10(12) viral genome particles/mouse of AAV-9 ΔR4-23/ΔC microdystrophin vector via tail vein to ~16-20-month-old (average 18.7-month-old) female mdx mice, a manifesting model of Duchenne cardiomyopathy. Cardiac transduction and heart function were examined at 2-8 months after gene transfer. We observed robust myocardial microdystrophin expression. Electrocardiography (ECG) and left ventricular catheter hemodynamic assays also revealed significant improvement. Furthermore, AAV-microdystrophin therapy prevented dobutamine-stress induced acute cardiac death. We demonstrate for the first time that AAV microdystrophin therapy significantly ameliorates functional deficiency in a phenotypic model of Duchenne cardiomyopathy. Our results support further exploration of microdystrophin therapy to treat Duchenne cardiomyopathy.
authors.affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, Missouri 65212, USA. duand@missouri.edu
authors.forename: Brian
authors.initials: B
authors.lastname: Bostick
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Shin
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yue
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Duan
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004280:Dobutamine / Q000009:adverse effects; D016189:Dystrophin / Q000235:genetics / Q000627:therapeutic use*; D004562:Electrocardiography; D005260:Female; D005822:Genetic Vectors; D006334:Heart Function Tests; D006439:Hemodynamics; D051379:Mice; D018101:Mice, Inbred mdx; D014161:Transduction, Genetic
chemical_list: D016189:Dystrophin; D004280:Dobutamine