Genetically Corrected iPSC-Derived Neural Stem Cell Grafts Deliver Enzyme Replacement to Affect CNS Disease in Sanfilippo B Mice.
Genetically Corrected iPSC-Derived Neural Stem Cell Grafts Deliver Enzyme Replacement to Affect CNS Disease in Sanfilippo B Mice.
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DOI：
10.1016/j.omtm.2018.06.005
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发表时间：
2018-09-21
期刊：
影响因子：
--
通讯作者：
Iacovino M
中科院分区：
文献类型：
--
作者：
Clarke D;Pearse Y;Kan SH;Le SQ;Sanghez V;Cooper JD;Dickson PI;Iacovino M
圣菲利波综合征B型（粘多糖沉积症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。目前没有治疗这种疾病的方法。在这里，我们报告说，离体，慢病毒校正Naglu−/−神经干细胞来自Naglu−/−小鼠（iNSC）纠正了他们的溶酶体病理，并允许他们分泌功能性NAGLU酶，可以采取由缺陷细胞。在将这些校正的iNSC长期移植到Naglu−/−小鼠中后，我们在大多数移植动物中检测到NAGLU活性。成功移植的Naglu−/−小鼠表现出储存物质的显著减少，星形胶质细胞活化的减少，以及移植细胞区域和邻近区域内小胶质细胞活化的完全预防，有益效果沿着脑的嘴尾轴沿着延伸到一半。我们的研究结果表明，iNSC在大脑中的长期植入能够交叉纠正Naglu−/−小鼠的病理学。我们的研究结果表明，基因工程的iNSC可能被用于提供酶和治疗MPS IIIB。
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-N-acetylglucosaminidase (NAGLU), leading to intralysosomal accumulation of heparan sulfate. There are currently no treatments for this disorder. Here we report that, ex vivo, lentiviral correction of Naglu−/− neural stem cells derived from Naglu−/− 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 Naglu−/− mice, we detected NAGLU activity in the majority of engrafted animals. Successfully transplanted Naglu−/− 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 Naglu−/− mice. Our findings suggest that genetically engineered iNSCs could potentially be used to deliver enzymes and treat MPS IIIB.
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早期神经变性与硫酸乙酰肝素在粘多糖糖化IIIB小鼠大脑中的小胶质细胞激活无关。
影响因子：
3.7
作者：
Ausseil, Jerome;Desmaris, Nathalie;Bigou, Stephanie;Attali, Ruben;Corbineau, Sebastien;Vitry, Sandrine;Parent, Mathieu;Cheillan, David;Fuller, Maria;Maire, Irene;Vanier, Marie-Therese;Heard, Jean-Michel
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Heard, Jean-Michel
DOI：
10.1073/pnas.1416660111
发表时间：
2014-10-14
影响因子：
11.1
作者：
Kan, Shih-hsin;Aoyagi-Scharber, Mika;Neufeld, Elizabeth F.
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Neufeld, Elizabeth F.
影响因子：
158.5
作者：
Kakkis, ED;Muenzer, J;Thompson, JN
通讯作者：
Thompson, JN
影响因子：
158.5
作者：
BARTON, NW;BRADY, RO;YU, KT
通讯作者：
YU, KT
DOI：
10.1016/j.omtm.2017.05.009
发表时间：
2017-09-15
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Aoyagi-Scharber M;Crippen-Harmon D;Lawrence R;Vincelette J;Yogalingam G;Prill H;Yip BK;Baridon B;Vitelli C;Lee A;Gorostiza O;Adintori EG;Minto WC;Van Vleet JL;Yates B;Rigney S;Christianson TM;Tiger PMN;Lo MJ;Holtzinger J;Fitzpatrick PA;LeBowitz JH;Bullens S;Crawford BE;Bunting S
通讯作者：
Bunting S