Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
Cell Transplant. 2012;21(7):1577-93. doi: 10.3727/096368912X636894.
Mucopolysaccharidosis type I (MPS-I; Hurler syndrome) is an inborn error of metabolism caused by lack of the functional lysosomal glycosaminoglycan (GAG)-degrading enzyme α-L-iduronidase (IDUA). Without treatment, the resulting GAG accumulation causes multisystem dysfunction and death within the first decade. Current treatments include allogeneic hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy. HSCT ameliorates clinical features and extends life but is not available to all patients, and inadequately corrects the most devastating features of the disease including mental retardation and skeletal deformities. Recent developments suggest that stem cells can be used to deliver needed enzymes to the central nervous system. To test this concept, we transplanted bone marrow-derived normal adult human MultiStem® cells into the cerebral lateral ventricles of immunodeficient MPS-I neonatal mice. Transplanted cells and human-specific DNA were detected in the hippocampal formation, striatum, and other areas of the central nervous system. Brain tissue assays revealed significant long-term decrease in GAG levels in the hippocampus and striatum. Sensorimotor testing 6 months after transplantation demonstrated significantly improved rotarod performance of transplanted mice in comparison to nontransplanted and sham-transplanted control animals. These results suggest that a single injection of MultiStem cells into the cerebral ventricles of neonatal MPS-I mice induces sustained reduction in GAG accumulation within the brain, and modest long-term improvement in sensorimotor function.
黏多糖贮积症 I 型（MPS-I；Hurler 综合征）是一种先天性代谢缺陷病，由缺乏功能性溶酶体糖胺聚糖（GAG）降解酶α-L-艾杜糖苷酸酶（IDUA）引起。如果不治疗，由此导致的 GAG 积累会导致多系统功能障碍，并在第一个十年内导致死亡。目前的治疗方法包括异体造血干细胞移植（HSCT）和酶替代疗法。HSCT 可改善临床症状并延长生命，但并非所有患者都适用，并且不能充分纠正疾病最具破坏性的特征，包括智力迟钝和骨骼畸形。最近的发展表明，干细胞可用于将所需的酶递送至中枢神经系统。为了验证这一概念，我们将骨髓来源的正常成人多能干细胞（MultiStem®细胞）移植到免疫缺陷型 MPS-I 新生小鼠的侧脑室内。在海马结构、纹状体和中枢神经系统的其他区域检测到移植细胞和人特异性 DNA。脑组织分析显示，海马体和纹状体中的 GAG 水平显著长期降低。移植后 6 个月的感觉运动测试显示，与未移植和假移植对照动物相比，移植小鼠的旋转棒性能显著提高。这些结果表明，将 MultiStem 细胞单次注射到新生 MPS-I 小鼠的侧脑室内，可诱导脑内 GAG 积累持续减少，并适度改善长期感觉运动功能。
