Wakabayashi Taichi, Shimada Yohta, Akiyama Kazumasa, Higuchi Takashi, Fukuda Takahiro, Kobayashi Hiroshi, Eto Yoshikatsu, Ida Hiroyuki, Ohashi Toya
1 Department of Pediatrics, Jikei University School of Medicine , Tokyo 105-8461, Japan .
2 Division of Gene Therapy, Research Center for Medical Sciences, Jikei University School of Medicine , Tokyo 105-8461, Japan .
Hum Gene Ther. 2015 Jun;26(6):357-66. doi: 10.1089/hum.2014.158. Epub 2015 Apr 20.
Mucopolysaccharidosis type II (MPS II) is a neuropathic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans (GAGs). We demonstrated that biochemical alterations in the brains of MPS II mice are not corrected by bone marrow transplantation (BMT) or enzyme replacement therapy, although BMT has been shown to be effective for other neurodegenerative MPSs, such as Hurler syndrome. In this study, we demonstrated that lentiviral isogeneic hematopoietic stem cell (HSC) gene therapy corrected neuronal manifestations by ameliorating lysosomal storage and autophagic dysfunction in the brains of MPS II mice. IDS-transduced HSCs increased enzyme activity both in various visceral organs and the CNS. Decreased levels of GAGs were observed in many organs, including cerebra, after transplantation of IDS-transduced HSCs. In addition, lentiviral HSC gene therapy normalized the secondary accumulation of autophagic substrates, such as p62 and ubiquitin-protein conjugates, in cerebra. Furthermore, in contrast to naive MPS II mice, there was no deterioration of neuronal function observed in transplant recipients. These results indicated that lentiviral HSC gene therapy is a promising approach for the treatment of CNS lesions in MPS II.
II型粘多糖贮积症（MPS II）是一种神经性溶酶体贮积症，由艾杜糖醛酸-2-硫酸酯酶（IDS）缺乏引起，导致糖胺聚糖（GAGs）蓄积。我们证明，尽管骨髓移植（BMT）已被证明对其他神经退行性MPSs（如Hurler综合征）有效，但MPS II小鼠大脑中的生化改变并不能通过骨髓移植或酶替代疗法得到纠正。在本研究中，我们证明慢病毒同基因造血干细胞（HSC）基因疗法通过改善MPS II小鼠大脑中的溶酶体贮积和自噬功能障碍来纠正神经元表现。转导IDS的造血干细胞在各种内脏器官和中枢神经系统中均增加了酶活性。在转导IDS的造血干细胞移植后，在包括大脑在内的许多器官中观察到GAGs水平降低。此外，慢病毒造血干细胞基因疗法使大脑中自噬底物（如p62和泛素-蛋白缀合物）的继发性蓄积正常化。此外，与未经处理的MPS II小鼠不同，在移植受体中未观察到神经元功能恶化。这些结果表明，慢病毒造血干细胞基因疗法是治疗MPS II中枢神经系统病变的一种有前景的方法。
