Engineered antibody therapies to counteract mutant huntingtin and related toxic intracellular proteins.
Engineered antibody therapies to counteract mutant huntingtin and related toxic intracellular proteins.
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DOI：
10.1016/j.pneurobio.2011.11.004
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发表时间：
2012-05
影响因子：
6.7
通讯作者：
Messer, Anne
中科院分区：
文献类型：
--
作者：
Butler, David C.;McLear, Julie A.;Messer, Anne
亨廷顿病(HD)疗法的工程抗体方法是基于这样一个前提，即显著降低主要错误折叠突变蛋白的水平将减少错误折叠亨廷顿蛋白(HTT)的异常蛋白质相互作用和直接毒性效应。这将反过来减少对细胞的病理性压力，并使固有的蛋白质平衡正常化。细胞内抗体(体内)是单链(ScFv)和单域(dab；纳米体)可变片段，可以保留全长抗体的亲和力和特异性，但可以作为基因进行选择和工程。在功能上，它们代表了一种基于蛋白质的方法来解决异常突变蛋白质折叠、翻译后修饰、蛋白质-蛋白质相互作用和聚集的问题。据报道，在细胞和器官培养物、果蝇和小鼠中，几种结合在突变体HTT的扩展的聚谷氨酰胺束两侧的体内可以改善突变的表型。对神经细胞内递送、细胞质折叠和长期疗效等困难挑战的进一步改进正在进行中。这篇综述涵盖了已发表的研究和新出现的方法，包括靶标的选择、选择和工程方法、基因和蛋白质输送选择以及细胞和动物模型中的候选测试。生成的抗体片段可用于HD的直接治疗和靶向验证/药物发现工具，同时该技术也适用于由有毒蛋白质引发的广泛的神经退行性疾病和其他疾病。
The engineered antibody approach to Huntington's disease (HD) therapeutics is based on the premise that significantly lowering the levels of the primary misfolded mutant protein will reduce abnormal protein interactions and direct toxic effects of the misfolded huntingtin (HTT). This will in turn reduce the pathologic stress on cells, and normalize intrinsic proteostasis. Intracellular antibodies (intrabodies) are single-chain (scFv) and single-domain (dAb; nanobody) variable fragments that can retain the affinity and specificity of full-length antibodies, but can be selected and engineered as genes. Functionally, they represent a protein-based approach to the problem of aberrant mutant protein folding, post-translational modifications, protein-protein interactions, and aggregation. Several intrabodies that bind on either side of the expanded polyglutamine tract of mutant HTT have been reported to improve the mutant phenotype in cell and organotypic cultures, fruit flies, and mice. Further refinements to the difficult challenges of intraneuronal delivery, cytoplasmic folding, and long-term efficacy are in progress. This review covers published studies and emerging approaches on the choice of targets, selection and engineering methods, gene and protein delivery options, and testing of candidates in cell and animal models. The resultant antibody fragments can be used as direct therapeutics and as target validation/drug discovery tools for HD, while the technology is also applicable to a wide range of neurodegenerative and other diseases that are triggered by toxic proteins.
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DOI：
10.1038/mt.2008.166
发表时间：
2008-10
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.3
作者：
Bateman, Jack R.;Lee, Anne M.;Wu, C. -ting
通讯作者：
Wu, C. -ting
影响因子：
6.1
作者：
Becher, MW;Kotzuk, JA;Ross, CA
通讯作者：
Ross, CA
影响因子：
2.4
作者：
Barkhordarian, Hedieh;Emadi, Sharareh;Sierks, Michael R.
通讯作者：
Sierks, Michael R.
影响因子：
6.1
作者：
Bortvedt, S. F.;McLear, J. A.;Wolfgang, W. J.
通讯作者：
Wolfgang, W. J.