Clarke Don, Pearse Yewande, Kan Shih-Hsin, Le Steven Q, Sanghez Valentina, Cooper Jonathan D, Dickson Patricia I, Iacovino Michelina
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Phoenix Nest Inc., P.O. Box 150057, Brooklyn, NY 11215, USA.
Mol Ther Methods Clin Dev. 2018 Jul 23;10:113-127. doi: 10.1016/j.omtm.2018.06.005. eCollection 2018 Sep 21.
Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB [MPS IIIB]) is a lysosomal storage disorder primarily affecting the brain that is caused by a deficiency in the enzyme α--acetylglucosaminidase (NAGLU), leading to intralysosomal accumulation of heparan sulfate. There are currently no treatments for this disorder. Here we report that, , lentiviral correction of neural stem cells derived from mice (iNSCs) corrected their lysosomal pathology and allowed them to secrete a functional NAGLU enzyme that could be taken up by deficient cells. Following long-term transplantation of these corrected iNSCs into mice, we detected NAGLU activity in the majority of engrafted animals. Successfully transplanted mice showed a significant decrease in storage material, a reduction in astrocyte activation, and complete prevention of microglial activation within the area of engrafted cells and neighboring regions, with beneficial effects extending partway along the rostrocaudal axis of the brain. Our results demonstrate long-term engraftment of iNSCs in the brain that are capable of cross-correcting pathology in mice. Our findings suggest that genetically engineered iNSCs could potentially be used to deliver enzymes and treat MPS IIIB.
B型Sanfilippo综合征（黏多糖贮积症IIIB型 [MPS IIIB]）是一种主要影响大脑的溶酶体贮积症，由α-N-乙酰氨基葡萄糖苷酶（NAGLU）缺乏引起，导致硫酸乙酰肝素在溶酶体内蓄积。目前尚无针对该疾病的治疗方法。在此我们报告，从小鼠中获得的诱导神经干细胞（iNSCs）经慢病毒校正后，纠正了它们的溶酶体病理状况，并使其分泌一种可被缺陷细胞摄取的功能性NAGLU酶。将这些校正后的iNSCs长期移植到小鼠体内后，我们在大多数移植成功的动物中检测到了NAGLU活性。成功移植的小鼠体内贮存物质显著减少，星形胶质细胞活化程度降低，在移植细胞区域及邻近区域内小胶质细胞活化完全得到预防，有益效果沿脑的前后轴部分延伸。我们的结果证明了iNSCs在大脑中的长期移植，其能够交叉纠正小鼠的病理状况。我们的研究结果表明，基因工程改造的iNSCs可能有潜力用于递送酶并治疗MPS IIIB。
