Osborn Mark J, McElmurry Ron T, Peacock Brandon, Tolar Jakub, Blazar Bruce R
University of Minnesota Cancer Center, Minneapolis, Minnesota, USA; Department of Pediatrics, Division of Bone Marrow Transplant, University of Minnesota, Minneapolis, Minnesota, USA.
University of Minnesota Cancer Center, Minneapolis, Minnesota, USA; Department of Pediatrics, Division of Bone Marrow Transplant, University of Minnesota, Minneapolis, Minnesota, USA.
Mol Ther. 2008 Aug;16(8):1459-1466. doi: 10.1038/mt.2008.119. Epub 2016 Dec 8.
Mucopolysaccharidosis type I (Hurler syndrome) is caused by a deficiency of the enzyme α-l-iduronidase (IDUA), and is characterized by widespread lysosomal glycosaminoglycan (GAG) accumulation. Successful treatment of central nervous system (CNS) diseases is limited by the presence of the blood-brain barrier, which prevents penetration of the therapeutic enzyme. Given that the brain capillary endothelial cells that form this barrier express high levels of the transferrin receptor (TfR), we hypothesized that the coupling of IDUA to transferrin (Tf) would facilitate IDUA delivery to the CNS. A plasmid bearing a fusion gene consisting of Tf and IDUA was constructed which, when delivered in vivo, resulted in the production of high levels of an enzymatically active protein that was transported into the CNS by TfR-mediated endocytosis. Short-term treatment resulted in a decrease in GAGs in the cerebellum of mucopolysaccharidosis type I (MPS I) mice. This approach, therefore, represents a potential strategy for the delivery of therapeutic enzyme to the CNS.
I型粘多糖贮积症（Hurler综合征）由α-L-艾杜糖醛酸酶（IDUA）缺乏引起，其特征是溶酶体中广泛的糖胺聚糖（GAG）蓄积。血脑屏障的存在限制了中枢神经系统（CNS）疾病的成功治疗，因为血脑屏障会阻止治疗性酶的渗透。鉴于形成该屏障的脑毛细血管内皮细胞表达高水平的转铁蛋白受体（TfR），我们推测将IDUA与转铁蛋白（Tf）偶联会促进IDUA向中枢神经系统的递送。构建了一个携带由Tf和IDUA组成的融合基因的质粒，当在体内递送时，该质粒会产生高水平的具有酶活性的蛋白质，该蛋白质通过TfR介导的内吞作用转运到中枢神经系统。短期治疗导致I型粘多糖贮积症（MPS I）小鼠小脑内的GAG减少。因此，这种方法代表了一种向中枢神经系统递送治疗性酶的潜在策略。
