Platt F M, Jeyakumar M, Andersson U, Priestman D A, Dwek R A, Butters T D, Cox T M, Lachmann R H, Hollak C, Aerts J M, Van Weely S, Hrebícek M, Moyses C, Gow I, Elstein D, Zimran A
Glycobiology Institute, Department of Biochemistry, University of Oxford, UK.
J Inherit Metab Dis. 2001 Apr;24(2):275-90. doi: 10.1023/a:1010335505357.
The glycosphingolipid (GSL) lysosomal storage diseases are caused by mutations in the genes encoding the glycohydrolases that catabolize GSLs within lysosomes. In these diseases the substrate for the defective enzyme accumulates in the lysosome and the stored GSL leads to cellular dysfunction and disease. The diseases frequently have a progressive neurodegenerative course. The therapeutic options for treating these diseases are relatively limited, and for the majority there are no effective therapies. The problem is further compounded by difficulties in delivering therapeutic agents to the brain. Most research effort to date has focused on strategies for augmenting enzyme levels to compensate for the underlying defect. These include bone marrow transplantation (BMT), enzyme replacement and gene therapy. An alternative strategy that we have been exploring is substrate deprivation. This approach aims to balance the rate of GSL synthesis with the impaired rate of GSL breakdown. The imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits the first step in GSL biosynthesis and has been used to evaluate this approach. Studies in an asymptomatic mouse model of Tay-Sachs disease have shown that substrate deprivation prevents GSL storage in the CNS. In a severe neurodegenerative mouse model of Sandhoff disease, substrate deprivation delayed the onset of symptoms and disease progression and significantly increased life expectancy. Combining NB-DNJ and BMT was found to be synergistic in the Sandhoff mouse model. A clinical trial in type I Gaucher disease has been undertaken and has shown beneficial effects. Efficacy was demonstrated on the basis of significant decreases in liver and spleen volumes, gradual but significant improvement in haematological parameters and disease activity markers, together with diminished GSL biosynthesis and storage as determined by independent biochemical assays. Further trials in type I Gaucher disease are in progress; studies are planned in patients with GSL storage in the CNS.
糖鞘脂（GSL）溶酶体贮积病是由编码糖水解酶的基因突变引起的，这些酶在溶酶体内分解代谢GSL。在这些疾病中，缺陷酶的底物在溶酶体中积累，储存的GSL导致细胞功能障碍和疾病。这些疾病通常具有进行性神经退行性病程。治疗这些疾病的选择相对有限，而且大多数情况下没有有效的治疗方法。将治疗药物输送到大脑的困难进一步加剧了这个问题。迄今为止，大多数研究工作都集中在提高酶水平以补偿潜在缺陷的策略上。这些策略包括骨髓移植（BMT）、酶替代疗法和基因治疗。我们一直在探索的另一种策略是底物剥夺。这种方法旨在平衡GSL合成速率与受损的GSL分解速率。亚氨基糖N-丁基脱氧野尻霉素（NB-DNJ）抑制GSL生物合成的第一步，并已用于评估这种方法。在泰-萨克斯病无症状小鼠模型中的研究表明，底物剥夺可防止中枢神经系统中GSL的储存。在桑德霍夫病严重神经退行性小鼠模型中，底物剥夺延迟了症状的发作和疾病进展，并显著延长了预期寿命。在桑德霍夫小鼠模型中发现，将NB-DNJ和BMT联合使用具有协同作用。已经对I型戈谢病进行了一项临床试验，并显示出有益效果。疗效通过肝脏和脾脏体积显著减小、血液学参数和疾病活动标志物逐渐但显著改善以及独立生化检测确定的GSL生物合成和储存减少得到证明。I型戈谢病的进一步试验正在进行中；计划对中枢神经系统中有GSL储存的患者进行研究。
