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携带人A53T α-突触核蛋白基因的AAV2/9在有无WPRE情况下的表达及毒性比较。

Comparison of the expression and toxicity of AAV2/9 carrying the human A53T α-synuclein gene in presence or absence of WPRE.

作者信息

Sun Xiuping, Yu Xuan, Zhang Ling, Zhao Wenjie, Wang Manshi, Zhang Yu, Li Xianglei, Gao Ran, Breger Ludivine S, Dovero Sandra, Porras Gregory, Fernagut Pierre-Olivier, Dehay Benjamin, Bezard Erwan, Qin Chuan

机构信息

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Peking Union Medical College (PUMC) & Institute of Laboratory Animal Science, Chinese Academy of Medical Science (CAMS), Beijing, China.

Univ. Bordeaux, CNRS, IMN, UMR 5293, F-33000 Bordeaux, France.

出版信息

Heliyon. 2021 Feb 17;7(2):e06302. doi: 10.1016/j.heliyon.2021.e06302. eCollection 2021 Feb.

DOI:10.1016/j.heliyon.2021.e06302
PMID:33665452
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7903312/
Abstract

Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) is thought to enhance transgene expression of target genes delivered by adeno-associated viral (AAV) vectors. This study assessed the protein expression of α-synuclein, phosphorylated α-synuclein at Serine 129, extent of nigrostriatal degeneration as well as subsequent behavioral deficits induced by unilateral intranigral stereotactic injection in male adult C57BL/6J mice of an AAV2/9 expressing A53T human α-synuclein under the control of the synapsin promoter in presence or absence of the WPRE. The presence of WPRE enabled to achieve greater nigrostriatal degeneration and synucleinopathy which was concomitant with worsened forelimb use asymmetry. This work refines a mouse Parkinson's disease model in which anatomo-pathology is related to behavioral deficits.

摘要

土拨鼠肝炎病毒转录后调控元件（WPRE）被认为可增强腺相关病毒（AAV）载体所传递的靶基因的转基因表达。本研究评估了在有或无WPRE的情况下，通过突触蛋白启动子控制表达A53T人α-突触核蛋白的AAV2/9对成年雄性C57BL/6J小鼠进行单侧黑质内立体定向注射后，α-突触核蛋白、丝氨酸129位点磷酸化α-突触核蛋白的蛋白表达、黑质纹状体变性程度以及随后诱导的行为缺陷。WPRE的存在能够导致更严重的黑质纹状体变性和突触核蛋白病，这与前肢使用不对称性恶化相关。这项工作优化了一种小鼠帕金森病模型，其中解剖病理学与行为缺陷相关。

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Comparison of the expression and toxicity of AAV2/9 carrying the human A53T α-synuclein gene in presence or absence of WPRE.携带人A53T α-突触核蛋白基因的AAV2/9在有无WPRE情况下的表达及毒性比较。
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Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies.转录因子 EB 过表达可预防实验性突触核蛋白病中的神经退行性变。
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Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson's disease.
Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies.
提高基于腺相关病毒的血友病基因治疗安全性和有效性的下一代策略：来自其他基因治疗临床试验的经验教训。
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Longitudinal assessment of motor function following the unilateral intrastriatal 6-hydroxydopamine lesion model in mice.小鼠单侧纹状体内6-羟基多巴胺损伤模型后运动功能的纵向评估
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