Lachmann Robin H
a Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Expert Rev Endocrinol Metab. 2009 May;4(3):217-224. doi: 10.1586/eem.09.8.
A number of lysosomal storage disorders (LSDs) are characterized by glycosphingolipid (GSL) storage in the brain. Although enzyme-replacement therapy is an effective treatment for the visceral manifestations of some of these disorders, this approach has not, to date, been useful in CNS disease. Substrate reduction therapy (SRT) is an alternative approach to treatment in which the aim is to reduce the rate of synthesis of GSL to a level where the residual enzyme activity in the affected cell can prevent lysosomal storage. Miglustat, an iminosugar, is an inhibitor of the first step of GSL synthesis and has been used successfully for SRT in Gaucher disease. Miglustat is a small molecule and can enter the brain. It has been shown to delay symptom onset and prolong life in a number of animal models of GSL LSDs. This review describes the current progress in the clinical development of SRT with miglustat for these disorders.
许多溶酶体贮积症（LSDs）的特征是脑内鞘糖脂（GSL）蓄积。尽管酶替代疗法是治疗其中一些疾病内脏表现的有效方法，但迄今为止，这种方法对中枢神经系统疾病并无用处。底物减少疗法（SRT）是一种替代治疗方法，其目的是将GSL的合成速率降低到受影响细胞中的残余酶活性能够防止溶酶体贮积的水平。米格列醇是一种亚氨基糖，是GSL合成第一步的抑制剂，已成功用于戈谢病的底物减少疗法。米格列醇是一种小分子，能够进入大脑。在多种GSL溶酶体贮积症的动物模型中，它已被证明可延缓症状出现并延长寿命。本综述描述了米格列醇用于这些疾病的底物减少疗法临床开发的当前进展。
