Wolfe J H, Sands M S, Barker J E, Gwynn B, Rowe L B, Vogler C A, Birkenmeier E H
Jackson Laboratory, Bar Harbor, Maine 04609.
Nature. 1992;360(6406):749-53. doi: 10.1038/360749a0.
An inherited deficiency of beta-glucuronidase in humans, mice and dogs causes mucopolysaccharidosis VII (Sly syndrome), a progressive degenerative disease that reduces lifespan (to an average of 5 months in mice) and results from lysosomal storage of undegraded glycosaminoglycans in the spleen, liver, kidney, cornea, brain and skeletal system. Bone marrow transplantation in mutant mice provides a source of normal enzyme ('cross-correction'), which substantially improves the clinical condition and extends the average lifespan to 18 months. Gene therapy by transfer of a beta-glucuronidase gene into mutant haematopoietic stem cells is an alternative approach, but it is not known whether the low expression of vector-transferred genes in vivo would be sufficiently effective. Here we show that retroviral vector-mediated transfer of the gene to mutant stem cells results in long-term expression of low levels of beta-glucuronidase which partially corrects the disease by reducing lysosomal storage in liver and spleen.
人类、小鼠和犬类中β-葡萄糖醛酸酶的遗传性缺乏会导致黏多糖贮积症VII型（斯利综合征），这是一种进行性退行性疾病，会缩短寿命（小鼠平均寿命缩短至5个月），其病因是未降解的糖胺聚糖在脾脏、肝脏、肾脏、角膜、大脑和骨骼系统的溶酶体中蓄积。对突变小鼠进行骨髓移植可提供正常酶的来源（“交叉校正”），这可显著改善临床状况并将平均寿命延长至18个月。将β-葡萄糖醛酸酶基因转移到突变造血干细胞中进行基因治疗是另一种方法，但尚不清楚载体转移基因在体内的低表达是否足够有效。我们在此表明，逆转录病毒载体介导的该基因向突变干细胞的转移导致β-葡萄糖醛酸酶低水平的长期表达，这通过减少肝脏和脾脏中的溶酶体贮积而部分纠正了该疾病。
