Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer
Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer
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DOI：
10.1073/pnas.222221899
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发表时间：
2002-10-15
影响因子：
11.1
通讯作者：
Shimada, T
中科院分区：
文献类型：
--
作者：
Takahashi, H;Hirai, Y;Shimada, T
法布里病是一种由溶酶体酶α-半乳糖苷酶A（α-gal A）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点。我们研究了基因介导的酶替代治疗法布里病的可行性。将含有α-gal A基因的腺相关病毒（AAV）载体注射到Fabry基因敲除小鼠的右侧股四头肌中。一项时间过程研究表明，血浆中的 α-gal A 活性增加到正常小鼠的大约 25%，并且这种升高的活性持续至少 30 周，而不会产生抗 α-gal A 抗体。经治疗的 Fabry 小鼠各器官中的 α-gal A 活性仍为正常小鼠中观察到的活性的 5-20%。注射载体后 25 周，这些器官中积累的三酰神经酰胺被完全清除。免疫组织化学和电子显微镜分析也证实了三酰神经酰胺球蛋白水平的降低。对接受治疗的小鼠进行超声心动图检查，显示治疗 25 周后心脏肥大的结构得到改善。 AAV载体介导的肌肉定向基因转移为法布里病提供了一种有效且实用的治疗方法。
Fabry disease is a systemic disease caused by genetic deficiency of a lysosomal enzyme, alpha-galactosidase A (alpha-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 alpha-gal A gene was injected into the right quadriceps muscles of Fabry knockout mice. A time course study showed that alpha-gal A activity in plasma was increased to approximate to25% of normal mice and that this elevated activity persisted for up to at least 30 weeks without development of anti-alpha-gal A antibodies. The alpha-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 globotriaosylceramide levels was also confirmed by immunohistochemical and electron microscopic 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.