Butters T D, Dwek R A, Platt F M
Glycobiology Institute, Department of Biochemistry, Oxford University, Oxford, UK.
Adv Exp Med Biol. 2003;535:219-26. doi: 10.1007/978-1-4615-0065-0_14.
Glycosphingolipid lysosomal storage diseases are a small but challenging group of human disorders to treat. Although these appear to be monogenic disorders where the catalytic activity of enzymes in glycosphingolipid catabolism is impaired, the presentation and severity of disease is heterogeneous. Treatment is often restricted to palliative care, but in some disorders enzyme replacement does offer a significant clinical improvement of disease severity. An alternative therapeutic approach termed "substrate deprivation" or "substrate reduction therapy" (SRT) aims to reduce cellular glycosphingolipid biosynthesis to match the impairment in catalytic activity seen in lysosomal storage disorders. N-Alkylated imino sugars are nitrogen containing polyhydroxylated heterocycles that have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramide-specific glucosyltransferase. The use of N-alkylated imino sugars to establish SRT as an alternative therapeutic strategy is described in cell culture and gene knockout mouse disease models. One imino sugar, N-butyl-DNJ (NB-DNJ) has been used in clinical trials for type 1 Gaucher disease and has shown to be an effective and safe therapy for this disorder. The results of these trials and the prospects of improvement to the design of imino sugar compounds for treating Gaucher and other glycosphingolipid lysosomal storage disorders will be discussed.
糖鞘脂溶酶体贮积病是一小类治疗起来颇具挑战性的人类疾病。尽管这些疾病看似是单基因疾病，即糖鞘脂分解代谢中酶的催化活性受损，但疾病的表现和严重程度却具有异质性。治疗通常局限于姑息治疗，但在某些疾病中，酶替代疗法确实能显著改善疾病的严重程度。另一种称为“底物剥夺”或“底物减少疗法”（SRT）的治疗方法旨在减少细胞内糖鞘脂的生物合成，以匹配溶酶体贮积病中所见的催化活性受损情况。N-烷基化亚氨基糖是含氮的多羟基杂环化合物，对真核细胞中鞘脂糖基化途径的第一种酶——神经酰胺特异性葡萄糖基转移酶具有抑制活性。在细胞培养和基因敲除小鼠疾病模型中描述了使用N-烷基化亚氨基糖来确立SRT作为一种替代治疗策略。一种亚氨基糖，N-丁基-DNJ（NB-DNJ）已用于1型戈谢病的临床试验，并已证明对该疾病是一种有效且安全的治疗方法。将讨论这些试验的结果以及改进亚氨基糖化合物设计以治疗戈谢病和其他糖鞘脂溶酶体贮积病的前景。
