Pharmacological chaperone therapy for Fabry disease.
Pharmacological chaperone therapy for Fabry disease.
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DOI：
10.2183/pjab.88.18
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Ishii S
中科院分区：
文献类型：
--
作者：
Ishii S
法布里病是一种由α-半乳糖苷酶A活性不足引起的遗传性溶酶体贮积性疾病。法布里病的许多错义突变常导致基因产物错误折叠，并通过质量控制系统滞留在内质网中；然后它们被内质网相关降解去除。我们发现一种有效的α-半乳糖苷酶a抑制剂，1-脱氧半乳糖烯霉素，作为一种药理学伴侣，通过结合其活性位点促进突变酶的适当折叠，从而提高其稳定性并在哺乳动物细胞中转运到溶酶体。对表达人α-半乳糖苷酶A突变体的转基因小鼠口服1-脱氧半乳糖苷吉霉素，可导致各器官α-半乳糖苷酶A活性显著升高，同时伴有球三烷基神经酰胺的减少，这与法布里病的病理有关。发现78个错义突变对1-脱氧半乳糖酸吉里霉素有反应。这些数据表明，许多法布里病患者可能从药物伴侣治疗中获益。
Fabry disease is an inherited lysosomal storage disorder caused by deficient α-galactosidase A activity. Many missense mutations in Fabry disease often cause misfolded gene products, which leads to their retention in the endoplasmic reticulum by the quality control system; they are then removed by endoplasmic reticulum-associated degradation. We discovered that a potent α-galactosidase A inhibitor, 1-deoxygalactonojirimycin, acts as a pharmacological chaperone to facilitate the proper folding of the mutant enzyme by binding to its active site, thereby improving its stability and trafficking to the lysosomes in mammalian cells. The oral administration of 1-deoxygalactonojirimycin to transgenic mice expressing human mutant α-galactosidase A resulted in significant increases in α-galactosidase A activity in various organs, with concomitant reductions in globotriaosylceramide, which contributes to the pathology of Fabry disease. Seventy-eight missense mutations were found to be responsive to 1-deoxygalactonojirimycin. These data indicate that many patients with Fabry disease could potentially benefit from pharmacological chaperone therapy.
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