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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer
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Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer

机译：腺相关病毒介导的肌肉定向基因转移在敲除小鼠中法布里病的长期全身治疗

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摘要

Fabry disease is a systemic disease caused by genetic deficiency of a lysosomal enzyme, α-galactosidase A (α-gal A), and is thought to be an important target for enzyme replacement therapy. We studied the feasibility of gene-mediated enzyme replacement for Fabry disease. The adeno-associated virus (AAV) vector containing the α-gal A gene was injected into the right quadriceps muscles of Fabry knockout mice. A time course study showed that α-gal A activity in plasma was increased to ≈25% of normal mice and that this elevated activity persisted for up to at least 30 weeks without development of anti-α-gal A antibodies. The α-gal A activity in various organs of treated Fabry mice remained 5-20% of those observed in normal mice. Accumulated globotriaosylceramide in these organs was completely cleared by 25 weeks after vector injection. Reduction of globotriaosykeramide levels was also confirmed by immunohistochemical and electronmicroscopic analyses. Echocardiographic examination of treated mice demonstrated structural improvement of cardiac hypertrophy 25 weeks after the treatment. AAV vector-mediated muscle-directed gene transfer provides an efficient and practical therapeutic approach for Fabry disease.
机译：法布里病是由溶酶体酶α-半乳糖苷酶A（α-galA）的遗传缺陷引起的全身性疾病，被认为是酶替代疗法的重要靶标。我们研究了法布里疾病的基因介导的酶替代的可行性。将含有α-galA基因的腺相关病毒（AAV）载体注射到法布里敲除小鼠的右四头肌中。一项时程研究表明，血浆中的α-galA活性增加到正常小鼠的≈25％，并且这种升高的活性持续了至少30周，没有产生抗α-galA抗体。在处理过的法布里小鼠的各种器官中，α-galA活性仍然是正常小鼠中观察到的5-20％。注射载体后25周，这些器官中积累的globotriaosylceramide被完全清除。免疫组织化学和电镜分析也证实了globotriaosykeramide水平的降低。处理过的小鼠的超声心动图检查显示，治疗后25周心脏肥大的结构改善。 AAV载体介导的肌肉定向基因转移为法布里（Fabry）疾病提供了一种有效而实用的治疗方法。

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