Urayama Akihiko, Grubb Jeffrey H, Sly William S, Banks William A
Department of Neurology, Laboratory of Protein Misfolding Disorders, University of Texas Medical Branch, Galveston, Texas, USA.
Mol Ther. 2008 Jul;16(7):1261-6. doi: 10.1038/mt.2008.84. Epub 2008 Apr 29.
Mucopolysaccharidosis type IIIA (MPS IIIA), which is a lysosomal storage disorder (LSD) caused by inherited deficiency of sulfamidase, is characterized by severe, progressive central nervous system (CNS) dysfunction. Enzyme replacement therapy (ERT) to treat CNS storage is challenging, because the access of enzymes to the brain is restricted by the blood-brain barrier (BBB). In a prior study, we found that phosphorylated beta-glucuronidase (P-GUS) could be transcytosed across the BBB in newborn mice by the mannose 6-phosphate (M6P) receptor. In order to determine whether sulfamidase can utilize this pathway, we examined brain influx and the specificity of uptake of sulfamidase after intravenous (i.v.) injection in 2-day-old and 8-week-old mice. [(131)I]Sulfamidase was transported across the BBB in neonates at rates higher than that of simultaneously injected [(125)I]albumin. In contrast, the transport of [(131)I]sulfamidase was negligible in 8-week-old mice, thereby showing that the BBB transport mechanism is developmentally downregulated. Capillary depletion revealed that 83.7% of the [(131)I]sulfamidase taken up by the brain was in the parenchyma, demonstrating transfer across the capillary wall. The uptake of [(131)I]sulfamidase into the brain was significantly reduced by co-injections of M6P and P-GUS. That is, the transport of sulfamidase into the brain parenchyma in early postnatal life is mediated by the M6P receptor, which is shared with P-GUS and is likely accessible to other M6P-containing lysosomal enzymes.
ⅢA型粘多糖贮积症（MPS IIIA）是一种由遗传性硫酸酯酶缺乏引起的溶酶体贮积病（LSD），其特征为严重的进行性中枢神经系统（CNS）功能障碍。酶替代疗法（ERT）用于治疗CNS贮积具有挑战性，因为酶进入大脑受到血脑屏障（BBB）的限制。在先前的一项研究中，我们发现磷酸化β-葡萄糖醛酸酶（P-GUS）可通过甘露糖6-磷酸（M6P）受体在新生小鼠中跨BBB进行转胞吞作用。为了确定硫酸酯酶是否可以利用这一途径，我们在2日龄和8周龄小鼠静脉注射（i.v.）后检测了硫酸酯酶的脑内流入量和摄取特异性。[（131）I]硫酸酯酶在新生儿中跨BBB转运的速率高于同时注射的[（125）I]白蛋白。相比之下，[（131）I]硫酸酯酶在8周龄小鼠中的转运可忽略不计，从而表明BBB转运机制在发育过程中下调。毛细血管清除显示，大脑摄取的[（131）I]硫酸酯酶中有83.7%存在于实质组织中，表明其穿过了毛细血管壁。同时注射M6P和P-GUS可显著降低[（131）I]硫酸酯酶进入大脑的摄取量。也就是说，出生后早期硫酸酯酶进入脑实质的转运是由M6P受体介导的，该受体与P-GUS共用，并且其他含M6P的溶酶体酶可能也可利用。
