Ohashi T, Watabe K, Sato Y, Saito I, Barranger J A, Matalon R, Eto Y
Department of Pediatrics, University of Tokyo, Japan.
Acta Paediatr Jpn. 1996 Apr;38(2):193-201. doi: 10.1111/j.1442-200x.1996.tb03468.x.
Metachromatic leukodystrophy (MLD) is an inherited metabolic disease which is characterized by a deficiency of arylsulfatase A (ASA). This deficiency causes progressive accumulation of cerebroside sulfate in oligodendrocytes (OL) in the brain, resulting in dysmyelination. Approaches being developed by the authors to treating MLD are based on direct delivery of ASA genes into the brain. In the present report, it has been shown that the recombinant adenovirus (Adex1SRLacZ) was able to transduce the OL very efficiently. Moreover, primary fibroblasts from MLD patients were exposed to recombinant adenovirus expressing the ASA gene (Adex1SRASA) and the cells expressed the transgene. The influence of overexpression of ASA on the activity of other sulfatases was also tested in fibroblasts from patients with MLD using a retrovirus vector (MFG-ASA). It was demonstrated that the overexpression of ASA reduces the activity of various sulfatases by a small amount but does not induce an accumulation of glycosaminoglycan. These results indicate that the influence of ASA overexpression on other sulfatases is different from that of the N-acetygalactosamine-4-sulfatase overexpression in a previous report. It was concluded that the correction of ASA deficiency by a recombinant adenovirus that potentially could be used to transfer the gene to the brain, and gene therapy for MLD based on gene transfer of the ASA gene to mutant cells will be feasible because the overexpression of ASA in cells does not lead to profound deficiency of other sulfatases or result in a new phenotype.
异染性脑白质营养不良（MLD）是一种遗传性代谢疾病，其特征是芳基硫酸酯酶A（ASA）缺乏。这种缺乏导致脑内少突胶质细胞（OL）中硫酸脑苷脂的进行性积累，从而导致髓鞘形成障碍。作者正在开发的治疗MLD的方法是基于将ASA基因直接导入大脑。在本报告中，已表明重组腺病毒（Adex1SRLacZ）能够非常有效地转导OL。此外，将MLD患者的原代成纤维细胞暴露于表达ASA基因的重组腺病毒（Adex1SRASA），细胞表达了转基因。还使用逆转录病毒载体（MFG-ASA）在MLD患者的成纤维细胞中测试了ASA过表达对其他硫酸酯酶活性的影响。结果表明，ASA的过表达会少量降低各种硫酸酯酶的活性，但不会诱导糖胺聚糖的积累。这些结果表明，ASA过表达对其他硫酸酯酶的影响与先前报告中N-乙酰半乳糖胺-4-硫酸酯酶过表达的影响不同。得出的结论是，通过重组腺病毒纠正ASA缺乏可能可用于将基因转移到大脑，并且基于将ASA基因转移到突变细胞的MLD基因治疗将是可行的，因为细胞中ASA的过表达不会导致其他硫酸酯酶的严重缺乏或产生新的表型。
