title: Microdystrophin ameliorates muscular dystrophy in the canine model of duchenne muscular dystrophy.
abstract: Dystrophin deficiency results in lethal Duchenne muscular dystrophy (DMD). Substituting missing dystrophin with abbreviated microdystrophin has dramatically alleviated disease in mouse DMD models. Unfortunately, translation of microdystrophin therapy has been unsuccessful in dystrophic dogs, the only large mammalian model. Approximately 70% of the dystrophin-coding sequence is removed in microdystrophin. Intriguingly, loss of ≥50% dystrophin frequently results in severe disease in patients. To test whether the small gene size constitutes a fundamental design error for large mammalian muscle, we performed a comprehensive study using 22 dogs (8 normal and 14 dystrophic). We delivered the ΔR2-15/ΔR18-19/ΔR20-23/ΔC microdystrophin gene to eight extensor carpi ulnaris (ECU) muscles in six dystrophic dogs using Y713F tyrosine mutant adeno-associated virus (AAV)-9 (2.6 × 10(13) viral genome (vg) particles/muscle). Robust expression was observed 2 months later despite T-cell infiltration. Major components of the dystrophin-associated glycoprotein complex (DGC) were restored by microdystrophin. Treated muscle showed less inflammation, fibrosis, and calcification. Importantly, therapy significantly preserved muscle force under the stress of repeated cycles of eccentric contraction. Our results have established the proof-of-concept for microdystrophin therapy in dystrophic muscles of large mammals and set the stage for clinical trial in human patients.
authors: Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, Missouri 65212, USA. duand@missouri.edu
authors: Jin-Hong
authors: JH
authors: Shin
authors: Xiufang
authors: X
authors: Pan
authors: Chady H
authors: CH
authors: Hakim
authors: Hsiao T
authors: HT
authors: Yang
authors: Yongping
authors: Y
authors: Yue
authors: Keqing
authors: K
authors: Zhang
authors: Ronald L
authors: RL
authors: Terjung
authors: Dongsheng
authors: D
authors: Duan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004285:Dogs; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D008297:Male; D051379:Mice; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000628:therapy*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000628:therapy*
chemical_list: D016189:Dystrophin