Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein
Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein
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DOI：
10.1073/pnas.93.24.14082
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发表时间：
1996-11-26
影响因子：
11.1
通讯作者：
Byrne, BJ
中科院分区：
文献类型：
--
作者：
Kessler, PD;Podsakoff, GM;Byrne, BJ
体细胞基因治疗已被提出作为一种手段来实现治疗蛋白的全身递送。然而，有有限的证据表明，目前的基因传递方法可以实际实现这一目标。在这项研究中，我们证明，将含有β -半乳糖苷酶（AAV-lacZ）基因的重组腺相关病毒（rAAV）载体单次肌内注射到成年BALB/c小鼠中，在肌纤维中检测到蛋白表达至少32周。将含有人促红细胞生成素（AAV-Epo）基因的AAV载体单次肌内注射到小鼠体内，可导致促红细胞生成素的剂量依赖性分泌和相应的红细胞生成增加，持续时间长达40周。用AAV-Epo载体体外转导的原代人肌管也显示出促红细胞生成素的剂量依赖性产生。这些结果表明，rAAV载体能够转导骨骼肌，并且能够在单次肌内给药后实现治疗性蛋白的持续表达和全身递送，使用AAV载体进行基因治疗可能为治疗遗传性和获得性蛋白缺乏症提供实用的策略。
Somatic gene therapy has been proposed as a means to achieve systemic delivery of therapeutic proteins. However, there is limited evidence that current methods of gene delivery can practically achieve this goal. In this study, we demonstrate that, following a single intramuscular administration of a recombinant adeno-associated virus (rAAV) vector containing the beta-galactosidase (AAV-lacZ) gene into adult BALB/c mice, protein expression was detected In myofibers for at least 32 weeks. A single intramuscular administration of an AAV vector containing a gene for human erythropoietin (AAV-Epo) into mice resulted in dose-dependent secretion of erythropoietin and corresponding increases in red blood cell production that persisted for up to 40 weeks, primary human myotubes transduced in vitro with the AAV-Epo vector also showed dose-dependent production of Epo, These results demonstrate that rAAV vectors are able to transduce skeletal muscle and are capable of achieving sustained expression and systemic delivery of a therapeutic protein following a single intramuscular administration, Gene therapy using AAV vectors may provide a practical strategy for the treatment of inherited and acquired protein deficiencies.