Therapeutic development for Canavan disease using patient iPSCs introduced with the wild-type ASPA gene.
Therapeutic development for Canavan disease using patient iPSCs introduced with the wild-type ASPA gene.
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使用引入野生型ASPA基因的患者iPSC对Canavan病的治疗开发。
DOI：
10.1016/j.isci.2022.104391
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发表时间：
2022-06-17
期刊：
影响因子：
5.8
通讯作者：
Shi, Yanhong
中科院分区：
文献类型：
--
作者：
Chao, Jianfei;Feng, Lizhao;Ye, Peng;Chen, Xianwei;Cui, Qi;Sun, Guihua;Zhou, Tao;Tian, E.;Li, Wendong;Hu, Weidong;Riggs, Arthur D.;Matalon, Reuben;Shi, Yanhong
Canavan病(CD)是一种破坏性的神经系统疾病，缺乏有效的治疗方法。由于CD是由天冬氨酸氨基转移酶(ASPA)基因突变引起的，我们通过慢病毒转导或CRISPR/Cas9介导的基因编辑将野生型(WT)ASPA基因导入患者IPSCs。然后，我们将表达ASPA的患者IPSCs(ASPA-CD IPSCs)分化为NPC，结果表明所得到的ASPA-CD NPC具有很强的ASPA酶活性。ASPA-CD核祖细胞能在移植的CD小鼠脑组织中存活。植入的ASPA-CD神经干细胞重建了CD小鼠大脑中的ASPA活性，降低了脑组织和脑脊液中异常升高的NAA水平，并挽救了移植CD小鼠的显著病理表型，包括海绵状变性、髓鞘形成缺陷和运动功能障碍。这些转基因的患者IPSC来源的NPC代表了CD的一种有前途的细胞治疗候选方案，CD是一种既没有治愈方法也没有标准治疗方法的疾病。将野生型aspa基因导入CD患者ipscs，使aspa-cd ipscs分化为具有较强aspa活性的aspa-cd神经干细胞。植入aspa-cd神经干细胞可挽救CD小鼠的主要疾病表型，脑脊液NAA水平可作为监测CD治疗结果的生物标志物；生物技术；人类疾病的生物技术
Canavan disease (CD) is a devastating neurological disease that lacks effective therapy. Because CD is caused by mutations of the aspartoacylase (ASPA) gene, we introduced the wild-type (WT) ASPA gene into patient iPSCs through lentiviral transduction or CRISPR/Cas9-mediated gene editing. We then differentiated the WT ASPA-expressing patient iPSCs (ASPA-CD iPSCs) into NPCs and showed that the resultant ASPA-CD NPCs exhibited potent ASPA enzymatic activity. The ASPA-CD NPCs were able to survive in brains of transplanted CD mice. The engrafted ASPA-CD NPCs reconstituted ASPA activity in CD mouse brains, reduced the abnormally elevated level of NAA in both brain tissues and cerebrospinal fluid (CSF), and rescued hallmark pathological phenotypes of the disease, including spongy degeneration, myelination defects, and motor function impairment in transplanted CD mice. These genetically modified patient iPSC-derived NPCs represent a promising cell therapy candidate for CD, a disease that has neither a cure nor a standard treatment. The wild-type ASPA gene was introduced into CD patient iPSCs to make ASPA-CD iPSCs ASPA-CD iPSCs were differentiated into ASPA-CD NPCs with potent ASPA activity Engrafted ASPA-CD NPCs could rescue major disease phenotypes in CD mice CSF NAA level can be used as a biomarker to monitor the treatment outcome for CD Neuroscience; Biotechnology; Biotechnology of human disorders
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影响因子：
5.3
作者：
Lotun A;Gessler DJ;Gao G
通讯作者：
Gao G
影响因子：
64.8
作者：
Liu, Guang-Hui;Qu, Jing;Suzuki, Keiichiro;Nivet, Emmanuel;Li, Mo;Montserrat, Nuria;Yi, Fei;Xu, Xiuling;Ruiz, Sergio;Zhang, Weiqi;Wagner, Ulrich;Kim, Audrey;Ren, Bing;Li, Ying;Goebl, April;Kim, Jessica;Soligalla, Rupa Devi;Dubova, Ilir;Thompson, James;Yates, John, III;Esteban, Concepcion Rodriguez;Sancho-Martinez, Ignacio;Izpisua Belmonte, Juan Carlos
通讯作者：
Izpisua Belmonte, Juan Carlos
影响因子：
6.1
作者：
Francis, Jeremy S.;Wojtas, Ireneusz;Markov, Vladimir;Gray, Steven J.;McCown, Thomas J.;Samulski, R. Jude;Bilaniuk, Larissa T.;Wang, Dah-Jyuu;De Vivo, Darryl C.;Janson, Christopher G.;Leone, Paola
通讯作者：
Leone, Paola
DOI：
10.3791/53583
发表时间：
2016-02-02
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Blair JD;Bateup HS;Hockemeyer DF
通讯作者：
Hockemeyer DF
DOI：
10.1073/pnas.0711983105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Lowry, W. E.;Richter, L.;Plath, K.
通讯作者：
Plath, K.