Program in Transplantation Biology, Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Mol Ther. 2012 Aug;20(8):1501-7. doi: 10.1038/mt.2012.111. Epub 2012 Jun 12.
Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle disease caused by mutations in the dystrophin gene. Adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment. Studies in animal models and human trials suggested that immune responses to AAV capsid proteins and transgene products prevented efficient gene therapy. In this study, we used widespread intramuscular (i.m.) injection to deliver AAV6-canine micro-dystrophin (c-µdys) throughout a group of skeletal muscles in dystrophic dogs given a brief course of commonly used immunosuppressants. Robust c-µdys expression was obtained for at least two years and was associated with molecular reconstitution of the dystrophin-glycoprotein complex (DGC) at the muscle membrane. Importantly, c-µdys expression was maintained for at least 18 months after discontinuing immunosuppression. The results obtained in a relevant preclinical model of DMD demonstrate feasibility of widespread AAV-mediated muscle transduction and transgene expression in the presence of transient immunosuppression to achieve molecular reconstitution that can be directly translated to human trials.
杜氏肌营养不良症（DMD）是一种致命的 X 连锁肌肉疾病，由肌营养不良蛋白基因的突变引起。腺相关病毒（AAV）载体介导的基因替代策略有望成为一种治疗方法。动物模型研究和人体试验表明，针对 AAV 衣壳蛋白和转基因产物的免疫反应阻止了有效的基因治疗。在这项研究中，我们使用广泛的肌肉内（i.m.）注射，在接受短期常用免疫抑制剂治疗的 DMD 犬的一组骨骼肌中传递 AAV6-犬微肌营养不良蛋白（c-µdys）。至少两年内获得了强大的 c-µdys 表达，并与肌肉膜上的肌营养不良蛋白糖蛋白复合物（DGC）的分子重建相关。重要的是，在停止免疫抑制后至少 18 个月仍能维持 c-µdys 的表达。在 DMD 的相关临床前模型中获得的结果证明了在短暂免疫抑制存在的情况下，广泛的 AAV 介导的肌肉转导和转基因表达的可行性，以实现可直接转化为人体试验的分子重建。
