A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder
A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder
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DOI：
10.1172/jci5542
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发表时间：
1999-02-01
影响因子：
15.9
通讯作者：
Proia, RL
中科院分区：
文献类型：
--
作者：
Liu, YJ;Wada, R;Proia, RL
鞘糖脂（GSL）降解的遗传缺陷导致一组称为GSL储存障碍的严重疾病。目前对大多数这些疾病没有有效的治疗方法。我们已经探索了一种新的治疗模式，底物剥夺疗法，通过构建小鼠的遗传模型。将异常积累GSL的山德霍夫病小鼠与GSL合成受阻的小鼠交配。同时存在GSL合成和降解缺陷的小鼠不再积累GSL，神经功能得到改善，寿命更长。然而，由于另一类底物寡糖的积累，这些小鼠最终发展为迟发性神经系统疾病。这些结果支持了底物剥夺疗法的有效性，也突出了一些局限性。
Inherited defects in the degradation of glycosphingolipids (GSLs) cause a group of severe diseases known as GSL storage disorders. There are currently no effective treatments for the majority of these disorders. We have explored a new treatment paradigm, substrate deprivation therapy, by constructing a genetic model in mice. Sandhoff's disease mice, which abnormally accumulate GSLs, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span. However, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results support the validity of the substrate deprivation therapy and also highlight some limitations.