β-Galactosidase deficiency: An approach to chaperone therapy
β-Galactosidase deficiency: An approach to chaperone therapy
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β-半乳糖苷酶缺乏症：伴侣疗法的一种方法
DOI：
10.1007/s10545-006-0287-y
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发表时间：
2006
影响因子：
4.2
通讯作者：
Yoshiyuki Suzuki
中科院分区：
文献类型：
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作者：
Yoshiyuki Suzuki
总结我们提出了一种新的分子治疗方法，以溶酶体疾病的严重神经系统表现。人们发现，一些低分子量化合物在体外作为溶酶体酶的竞争性抑制剂，可以作为分子伴侣稳定和恢复酶分子的催化活性。我们首先使用半乳糖和1-脱氧半乳糖野尻霉素在法布里病（全身性血管病变）中开始了这项试验，然后使用新开发的化合物N-辛基-4-表-β-维列胺（NOEV）在β-半乳糖苷酶缺乏症（β-半乳糖苷酶病）伴全身性神经躯体和/或全身性骨骼表现（GM 1-神经节苷脂沉积症和Morquio B病）中开始了这项试验。这种伴侣化合物的管理导致在培养的成纤维细胞从患者和基因工程模型小鼠的细胞内酶活性的升高。此外，NOEV通过血脑屏障进入脑组织后，底物储存得到改善。我们希望这种新方法（化学伴侣疗法）将对某些β-半乳糖苷沉积症和其他可能累及中枢神经系统的溶酶体贮积病患者有用。
SummaryWe propose a new molecular therapeutic approach to lysosomal diseases with severe neurological manifestations. Some low-molecular-weight compounds, acting as competitive inhibitors of a lysosomal enzyme in vitro, were found to stabilize and restore catalytic activities of the enzyme molecule as a molecular chaperone. We started this trial first in Fabry disease (generalized vasculopathy) using galactose and 1-deoxygalactonojirimycin, and then in β-galactosidase deficiency disorders (β-galactosidosis) with generalized neurosomatic and/or systemic skeletal manifestations (GM1-gangliosidosis and Morquio B disease), using a newly developed chemical compound N-octyl-4-epi-β-valienamine (NOEV). Administration of this chaperone compound resulted in elevation of intracellular enzyme activity in cultured fibroblasts from patients and genetically engineered model mice. In addition, substrate storage was improved after NOEV had been transported into the brain tissue via the blood–brain barrier. We hope this new approach (chemical chaperone therapy) will be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.