Platt F M, Butters T D
Glycobiology Institute, Department of Biochemistry, University of Oxford, UK.
Biochem Pharmacol. 1998 Aug 15;56(4):421-30. doi: 10.1016/s0006-2952(98)00115-4.
The glycosphingolipid (GSL) lysosomal storage diseases result from mutations in the genes that encode the enzymes required for glycosphingolipid catabolism within lysosomes. They are relatively rare diseases, but are frequently severe in terms of their pathology. Many involve progressive neurodegeneration, and in the most severe forms result in death in early infancy. The therapeutic options for treating these diseases are limited, and for the majority of these disorders there are currently no therapies available. To date, most research has focused on correcting the genetic lesion by gene therapy or by augmenting the enzyme activity deficient in these patients by introducing fully functional enzyme. This can be achieved by bone marrow transplantation or intravenous infusion of purified or recombinant enzyme (enzyme replacement). Gene therapy and enzyme replacement therapy are disease specific, and pharmacological approaches for the treatment of these disorders have not been fully explored. In this commentary, the problems associated with disease therapy are discussed, and a pharmacological agent (N-butyldeoxynojirimycin) is presented for the potential generic treatment of this family of disorders. Successful prevention of glycosphingolipid storage in a mouse model of Tay-Sachs disease suggests that this strategy merits clinical evaluation.
鞘糖脂（GSL）溶酶体贮积病是由编码溶酶体内鞘糖脂分解代谢所需酶的基因突变引起的。它们是相对罕见的疾病，但就其病理学而言通常较为严重。许多疾病涉及进行性神经退行性变，最严重的形式会导致婴儿早期死亡。治疗这些疾病的选择有限，目前大多数这类疾病尚无可用的治疗方法。迄今为止，大多数研究集中在通过基因治疗纠正基因损伤，或通过引入功能完全正常的酶来增强这些患者体内缺乏的酶活性。这可以通过骨髓移植或静脉输注纯化或重组酶（酶替代疗法）来实现。基因治疗和酶替代疗法是针对特定疾病的，治疗这些疾病的药理学方法尚未得到充分探索。在这篇评论中，讨论了与疾病治疗相关的问题，并提出了一种药理学药物（N-丁基脱氧野尻霉素）用于这类疾病的潜在通用治疗。在泰-萨克斯病小鼠模型中成功预防鞘糖脂蓄积表明该策略值得进行临床评估。
