Cellular fusion for gene delivery to SCA1 affected Purkinje neurons.
Cellular fusion for gene delivery to SCA1 affected Purkinje neurons.
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DOI：
10.1016/j.mcn.2011.03.003
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发表时间：
2011-05
影响因子：
3.5
通讯作者：
Zheng, Tong
中科院分区：
文献类型：
--
作者：
Chen, K. Amy;Cruz, Pedro E.;Lanuto, Derek J.;Flotte, Terence R.;Borchelt, David R.;Srivastava, Arun;Zhang, Jianyi;Steindler, Dennis A.;Zheng, Tong
关键词：
小脑浦肯野神经元（PNs）具有与骨髓源性细胞（bmdc）融合的良好倾向，产生具有浦肯野细胞身份的异核体。这为遗传性共济失调（包括脊髓小脑性共济失调1型（SCA1））患者中处于危险或退行性PNs的挽救/修复提供了潜力，通过BMDCs引入治疗因子可能阻止或逆转疾病进展。在这项研究中，我们在Sca1154Q/2Q敲入小鼠模型中，结合基因治疗和基于干细胞的治疗，试图通过细胞-细胞融合修复危险的PNs。利用腺相关病毒载体7 （AAV7）对造血干细胞（HSC）群体富集的BMDCs进行基因修饰，使其携带SCA1修饰基因，并移植到辐射后的sc1154q /2Q小鼠体内。检测到供体Y染色体性别不匹配的双核浦肯野异核体，并成功在体内表达了修饰基因。新基因组在浦肯野异核体中的潜在影响被评估，使用核包裹体（NIs）作为反映SCA1疾病过程可能改变的生物学标记。在sc1154q /2Q治疗组中，观察到NIs数量总体减少，存活的PNs数量增加。此外，伯格曼胶质细胞被发现具有与供体群体融合的潜力，并揭示了另一种进入SCA1小脑危险细胞的治疗途径。本研究向将体细胞融合事件与神经保护基因治疗方法相结合的原理证明迈出了第一步，为各种神经退行性疾病提供潜在的神经元保护/修复。
Cerebellar Purkinje neurons (PNs) possess a well characterized propensity to fuse with bone marrow-derived cells (BMDCs), producing heterokaryons with Purkinje cell identities. This offers the potential to rescue/repair at risk or degenerating PNs in the inherited ataxias, including Spinocerebellar Ataxia 1 (SCA1), by introducing therapeutic factors through BMDCs to potentially halt or reverse disease progression. In this study, we combined gene therapy and a stem cell-based treatment to attempt repair of at-risk PNs through cell-cell fusion in a Sca1154Q/2Q knock-in mouse model. BMDCs enriched for the hematopoietic stem cell (HSC) population were genetically modified using adeno-associated viral vector 7 (AAV7) to carry SCA1 modifier genes and transplanted into irradiated Sca1154Q/2Q mice. Binucleated Purkinje heterokaryons with sex-mismatched donor Y chromosomes were detected and successfully expressed the modifier genes in vivo. Potential effects of the new genome within Purkinje heterokaryons were evaluated using nuclear inclusions (NIs) as a biological marker to reflect possible modifications of the SCA1 disease process. An overall decrease in number of NIs and an increase in the number of surviving PNs were observed in treated Sca1154Q/2Q. Furthermore, Bergmann glia were found to have fusogenic potential with the donor population and reveal another potential route of therapeutic entry into at-risk cells of the SCA1 cerebellum. This study presents a first step towards a proof of principle that combines somatic cellular fusion events with a neuroprotective gene therapy approach for providing potential neuronal protection/repair in a variety of neurodegenerative disorders.
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影响因子：
5.2
作者：
Chen, K. Amy;Lanuto, Derek;Steindler, Dennis A.
通讯作者：
Steindler, Dennis A.
影响因子：
5.2
作者：
Jessberger, Sebastian;Clemenson, Gregory D., Jr.;Gage, Fred H.
通讯作者：
Gage, Fred H.
影响因子：
64.8
作者：
Alvarez-Dolado, M;Pardal, R;Alvarez-Buylla, A
通讯作者：
Alvarez-Buylla, A
影响因子：
3.5
作者：
Del Monte, U
通讯作者：
Del Monte, U
影响因子：
64.5
作者：
Lam, Yung C.;Bowman, Aaron B.;Zoghbi, Huda Y.
通讯作者：
Zoghbi, Huda Y.