Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A
Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A
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DOI：
10.1016/j.ymthe.2005.09.017
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发表时间：
2006-02-01
影响因子：
12.4
通讯作者：
Richard, I
中科院分区：
文献类型：
--
作者：
Bartoli, M;Roudaut, C;Richard, I
钙蛋白酶病（肢带型肌营养不良症 2A 型，LGMD2A）是一种隐性肌肉疾病，由钙依赖性半胱氨酸蛋白酶钙蛋白酶 3 缺乏引起。迄今为止，尚无针对这种疾病的治疗方法。我们评估了重组腺相关病毒 (rAAV) 载体在 LGMD2A 小鼠模型中进行基因治疗的潜力。为了驱动钙蛋白酶 3 的表达，我们使用 rAAV2/1 假型载体和肌肉特异性启动子以避免钙蛋白酶 3 细胞毒性。我们报告了肌肉中高效稳定的转基因表达，恢复了蛋白水解活性，并且没有明显的毒性。此外，钙蛋白酶 3 正确靶向肌节。此外，它的存在导致了组织学特征的改善和生理水平的治疗功效，包括纠正萎缩和完全挽救收缩力缺陷。我们的结果证实了 AAV 介导的钙蛋白酶 3 基因转移作为治疗方法的可行性。
Calpainopathy (limb-girdle muscular dystrophy type 2A, LGMD2A) is a recessive muscular disorder caused by deficiency in the calcium-dependent cysteine protease calpain 3. To date, no treatment exists for this disease. We evaluated the potential of recombinant adeno-associated virus (rAAV) vectors for gene therapy in a murine model for LGMD2A. To drive the expression of calpain 3, we used rAAV2/1 pseudotyped vectors and muscle-specific promoters to avoid calpain 3 cell toxicity. We report efficient and stable transgene expression in muscle with restoration of the proteolytic activity and without evident toxicity. In addition, calpain 3 was correctly targeted to the sarcomere. Moreover, its presence resulted in improvement of the histological features and in therapeutic efficacy at the physiological levels, including correction of atrophy and full rescue of the contractile force deficits. Our results establish the feasibility of AAV-mediated calpain 3 gene transfer as a therapeutic approach.