Screening for pharmacological chaperones in Fabry disease
Screening for pharmacological chaperones in Fabry disease
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DOI：
10.1016/j.bbrc.2007.05.082
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发表时间：
2007-07-20
影响因子：
3.1
通讯作者：
Kaneski, Christine R.
中科院分区：
文献类型：
--
作者：
Shin, Sang-Hoon;Murray, Gary J.;Kaneski, Christine R.
作为Fabry病药物伴侣疗法(PCT)临床试验的先决条件，我们开发了一种快速筛选方法，用于增强患者来源细胞中内源性α-半乳糖苷酶A(α-GalA)的表达。我们使用基于T细胞的系统来筛选11个导致Fabry病的突变，并使用1-脱氧半乳糖吉利霉素(DGJ)进行增强。当患者来源的T细胞在DGJ存在的情况下培养时，α-GalA活性在几个突变中增加到正常的50%以上，但在其他突变中不受影响。除先前报道的突变R301Q外，A97V、R112H、R112C、A143T和L300P可增强，但R356W、G132R、A143P、R220X和30delG不能。所获得的α-GalA活性水平为DGJ在具有类似增强酶的患者中的治疗试验提供了基础。该检测方法在其他疾病中评价PCT对突变蛋白活性增强的程度具有普遍的实用价值。由爱思唯尔公司出版。
As a prerequisite for clinical trials of pharmacological chaperone therapy (PCT) for Fabry disease, we developed a rapid screening assay for enhancement of endogenous, alpha-galactosidase A (alpha-Gal A) in patient-derived cells. We used a T-cell based system to screen 11 mutations causing Fabry disease for enhanceability using 1-deoxygalactonojirimycin (DGJ). When patient-derived T-cells were grown in the presence of DGJ, alpha-Gal A activity increased to more than 50%, of normal in several mutations but was unaffected in others. In addition to the mutation R301Q, reported previously, A97V, R112H, R112C, A143T, and L300P were enhanceable, but R356W, G132R, A143P, R220X, and 30delG were not. The level of alpha-Gal A activity achieved provides a basis for the therapeutic trial of DGJ in patients with similarly enhanceable enzyme. This assay method has general utility in other disorders in assessing the degree of enhancement of activity of mutated proteins by PCT. Published by Elsevier Inc.