Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
Mol Cells. 2010 Jul;30(1):13-8. doi: 10.1007/s10059-010-0083-2. Epub 2010 Jul 14.
Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked inherited disorder caused by a deficiency of the enzyme iduronate-2-sulfatase (IDS), which results in the lysosomal accumulation of glycosaminoglycans (GAG) such as dermatan and heparan sulfate. Here, we report the generation of IDS knockout mice, a model of human MPS II, and an analysis of the resulting phenotype. We also evaluated the effect of gene therapy with a pseudotyped, recombinant adeno-associated virus 2/8 vector encoding the human IDS gene (rAAV-hIDS) in IDS-deficient mice. IDS activity and GAG levels were measured in serum and tissues after therapy. Gene therapy completely restored IDS activity in plasma and tissue of the knockout mice. The rescued enzymatic activity completely cleared the accumulated GAGs in all the tissues analyzed. This model can be used to explore the therapeutic potential of IDS replacement and other strategies for the treatment of MPS II. Additionally, AAV2/8 vectors have promising future clinical applications for the treatment of patients with MPS II.
黏多糖贮积症 II 型（MPS II；亨特综合征）是一种 X 连锁遗传性疾病，由溶酶体中缺乏艾杜糖-2-硫酸酯酶（IDS）引起，导致糖胺聚糖（GAG）如硫酸皮肤素和硫酸乙酰肝素的积累。在这里，我们报告了 IDS 敲除小鼠的产生，这是人类 MPS II 的模型，并分析了由此产生的表型。我们还评估了用编码人 IDS 基因的假型重组腺相关病毒 2/8 载体（rAAV-hIDS）进行基因治疗对 IDS 缺陷型小鼠的效果。治疗后在血清和组织中测量 IDS 活性和 GAG 水平。基因治疗完全恢复了敲除小鼠血浆和组织中的 IDS 活性。恢复的酶活性完全清除了所有分析组织中积累的 GAG。该模型可用于探索 IDS 替代治疗和其他治疗 MPS II 策略的治疗潜力。此外，AAV2/8 载体具有治疗 MPS II 患者的有前途的临床应用前景。
