Fiber-modified adenovirus for central nervous system Parkinson's disease gene therapy.
Fiber-modified adenovirus for central nervous system Parkinson's disease gene therapy.
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DOI：
10.3390/v6083293
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发表时间：
2014-08-21
期刊：
影响因子：
--
通讯作者：
Curiel DT
中科院分区：
文献类型：
--
作者：
Lewis TB;Glasgow JN;Harms AS;Standaert DG;Curiel DT
神经系统疾病的基因疗法继续蓬勃发展。随着疾病机制的阐明，这些方法的安全性和有效性需要结合转录调控元件、治疗基因和靶向递送的灵活基因递送平台。基于腺病毒血清型5（Ad 5）的载体可以携带大的遗传有效载荷以提供这种灵活性，但不能有效地抑制神经元细胞。为了解决这个问题，我们已经开发了一种向性修饰的Ad 5载体，具有神经元选择性靶向特性，用于帕金森病治疗模型的评估。在神经母细胞瘤细胞系模型系统中筛选一组向性修饰的Ad 5载体以增强基因递送。我们利用这些观察结果设计并构建了一个无偏见的Ad载体平台，该平台由未修饰的Ad 5和含有犬Ad血清型2纤维球结构域的向性修饰的Ad 5载体（Ad 5-CGW-CK 2）组成。传递到黑质或纹状体表明，这种载体产生了神经元限制的基因表达模式。许多转导的神经元来自具有到注射部位的传入投射的区域，这意味着载体结合突触前末梢，导致突触前转导。我们发现Ad 5-CGW-CK 2可以选择性地激活大脑中的神经元，并假设这种模块化平台可能适用于临床应用。
Gene-based therapies for neurological diseases continue to develop briskly. As disease mechanisms are elucidated, flexible gene delivery platforms incorporating transcriptional regulatory elements, therapeutic genes and targeted delivery are required for the safety and efficacy of these approaches. Adenovirus serotype 5 (Ad5)-based vectors can carry large genetic payloads to provide this flexibility, but do not transduce neuronal cells efficiently. To address this, we have developed a tropism-modified Ad5 vector with neuron-selective targeting properties for evaluation in models of Parkinson disease therapy. A panel of tropism-modified Ad5 vectors was screened for enhanced gene delivery in a neuroblastoma cell line model system. We used these observations to design and construct an unbiased Ad vector platform, consisting of an unmodified Ad5 and a tropism-modified Ad5 vector containing the fiber knob domain from canine Ad serotype 2 (Ad5-CGW-CK2). Delivery to the substantia nigra or striatum showed that this vector produced a neuronally-restricted pattern of gene expression. Many of the transduced neurons were from regions with afferent projections to the injection site, implicating that the vector binds the presynaptic terminal resulting in presynaptic transduction. We show that Ad5-CGW-CK2 can selectively transduce neurons in the brain and hypothesize that this modular platform is potentially adaptable to clinical use.
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影响因子：
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作者：
Jacobson, Samuel G.;Cideciyan, Artur V.;Ratnakaram, Ramakrishna;Heon, Elise;Schwartz, Sharon B.;Roman, Alejandro J.;Peden, Marc C.;Aleman, Tomas S.;Boye, Sanford L.;Sumaroka, Alexander;Conlon, Thomas J.;Calcedo, Roberto;Pang, Ji-Jing;Erger, Kirsten E.;Olivares, Melani B.;Mullins, Cristina L.;Swider, Malgorzata;Kaushal, Shalesh;Feuer, William J.;Iannaccone, Alessandro;Fishman, Gerald A.;Stone, Edwin M.;Byrne, Barry J.;Hauswirth, William W.
通讯作者：
Hauswirth, William W.
影响因子：
8.6
作者：
Bjorklund, Tomas;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.
DOI：
10.1007/978-1-61779-370-7_18
发表时间：
2011-01-01
期刊：
ADENO-ASSOCIATED VIRUS: METHODS AND PROTOCOLS
影响因子：
--
作者：
High, Katherine A.;Aubourg, Patrick
通讯作者：
Aubourg, Patrick
影响因子：
2.9
作者：
Chamberlin, NL;Du, B;Saper, CB
通讯作者：
Saper, CB
影响因子：
8.6
作者：
Bartus, Raymond T.;Herzog, Christopher D.;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.