San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11.
Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.
脑硫脂沉积病（MLD）是一种由于芳香硫酸酯酶 A（ARSA）缺乏引起的遗传性溶酶体贮积病。MLD 患者表现出进行性运动和认知障碍，并在症状出现后的几年内死亡。我们使用慢病毒载体将功能性 ARSA 基因转移到三个有晚发性婴儿型 MLD 的遗传、生化和神经生理学证据的无症状患者的造血干细胞（HSCs）中。在基因修正的 HSCs 再输注后，患者表现出广泛而稳定的 ARSA 基因替换，这导致在整个造血谱系和脑脊液中均有高酶表达。载体整合分析未发现异常克隆行为的证据。在预测的症状出现年龄之后的 7 至 21 个月，这三个患者均未出现或进展为该疾病。这些发现表明，慢病毒载体可实现对人造血系统的广泛基因工程改造，并且这种方法可能为 MLD 患者提供治疗益处。
