Coating of adeno-associated virus with reactive polymers can ablate virus tropsim, enable retargeting and provide resistance to neutralising antisera
Coating of adeno-associated virus with reactive polymers can ablate virus tropsim, enable retargeting and provide resistance to neutralising antisera
复制标题
DOI：
10.1002/jgm.1161
复制
发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Fisher, Kerry D.
中科院分区：
文献类型：
--
作者：
Carlisle, Robert C.;Benjamin, Reuben;Fisher, Kerry D.
背景基于聚- [N-（2-羟丙基）甲基丙烯酰胺]（HPMA）的共聚物先前已用于能够靶向递送腺病毒。在这里，我们证明聚合物涂层技术也可以用来修改和重定向腺相关病毒（AAV）5型和8型。方法三种策略修改AAV的转导靶向。第一种涉及AAV 5或AAV 8与氨基反应性HPMA共聚物的直接反应。第二种方法使用碳二亚胺（EDC）化学来增加AAV 5衣壳上的表面氨基的数目，从而提高涂覆效率。第三种方法是从衣壳蛋白中分离AAV 5基因组，并将其导入由聚乙烯亚胺（PEI）和HPMA组成的合成复合物中。涂层抑制唾液酸依赖性感染，并提供了一个平台，通过新的配体，包括碱性成纤维细胞生长因子的重靶向。重定向感染显示对中和抗血清部分耐药。使用PEI和HPMA递送AAV 5基因组是有效的，并且提供了对向性的绝对控制和抗血清的保护。与此相反，AAV 8可以直接与HPMA共聚物反应，并允许通过表皮生长因子受体的特异性重定向，但没有对中和antisever.Conclusions提供保护反应HPMA聚合物可用于消融两个AAV 8和EDC修饰的AAV 5的天然向性，并通过掺入靶向配体使受体特异性感染。这些数据显示转导靶向策略可用于改善AAV载体的多功能性。版权所有（c）2008约翰威利父子有限公司。
Background Copolymers based on poly- [N-(2-hydroxypropyl) methacrylamide] (HPMA) have been used previously to enable targeted delivery of adenovirus. Here we demonstrate polymer-coating techniques can also be used to modify and retarget adeno-associated virus (AAV) types 5 and 8.Methods Three strategies for modifying transductional targeting of AAV were employed. The first involved direct reaction of AAV5 or AAV8 with amino-reactive HPMA copolymer. The second approach used carbodiimide (EDC) chemistry to increase the number of surface amino groups on the AAV5 capsid, thereby improving coating efficiency. in the third approach, the AAV5 genome was isolated from capsid proteins and delivered in a synthetic polyplex consisting of polyethylenimine (PEI) and HPMA.Results Efficient covalent attachment of HPMA copolymer to AAV5 could only be achieved following modification of the virus with EDC. Coating inhibited sialic acid dependent infection and provided a platform for retargeting via new ligands, including basic fibroblast growth factor. Retargeted infection was shown to be partially resistant to neutralising antisera. Delivery of AAV5 genomes using PEI and HPMA was efficient and provided absolute control of tropism and protection from antisera. In contrast AAV8 could be reacted directly with HPMA copolymer and allowed specific retargeting via the epidermal growth factor receptor, but gave no protection against neutralising antisera.Conclusions Reactive HPMA polymers can be used to ablate the natural tropism of both AAV8 and EDC-modified AAV5 and enable receptor-specific infection by incorporation of targeting ligands. These data show transductional targeting strategies can be used to improve the versatility of AAV vectors. Copyright (c) 2008 John Wiley & Sons, Ltd.