Designer gene delivery vectors: molecular engineering and evolution of adeno-associated viral vectors for enhanced gene transfer.
Designer gene delivery vectors: molecular engineering and evolution of adeno-associated viral vectors for enhanced gene transfer.
复制标题
设计师基因递送向量：腺相关病毒载体的分子工程和进化，以增强基因转移。
DOI：
10.1007/s11095-007-9431-0
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发表时间：
2008-03
影响因子：
3.7
通讯作者：
Schaffer, David V.
中科院分区：
文献类型：
--
作者：
Kwon, Inchan;Schaffer, David V.
基于腺相关病毒（AAV）的基因传递载体是非常有前途的，因为这种亲本病毒具有几个令人满意的特征，包括缺乏致病性，有效感染分裂和非分裂细胞，以及持续维持病毒基因组。然而，为了提高AAV载体的效用，特别是基于AAV2（最具特征的AAV血清型）的载体，需要解决几个问题。首先，改变病毒的趋向性将有利于扩大其在各种组织或细胞类型中的应用。为了满足这一需求，载体假分型、镶嵌衣壳和靶向配体插入衣壳显示出改变AAV特异性的希望。此外，尽管对病毒结构-功能关系的了解有限，但文库选择和定向进化最近成为调节AAV向性的有希望的方法。其次，要成功应用AAV载体，必须解决对AAV预先存在的免疫问题。“屏蔽”聚合物、定点诱变和其他AAV血清型在避免免疫中和方面取得了成功。此外，AAV衣壳的定向进化是一种高通量方法，已经产生了对中和抗体具有实质性抗性的载体。因此，分子工程和AAV载体的定向进化为产生具有增强特性的“设计”基因传递载体提供了希望。
Gene delivery vectors based on adeno-associated virus (AAV) are highly promising due to several desirable features of this parent virus, including a lack of pathogenicity, efficient infection of dividing and non-dividing cells, and sustained maintenance of the viral genome. However, several problems should be addressed to enhance the utility of AAV vectors, particularly those based on AAV2, the best characterized AAV serotype. First, altering viral tropism would be advantageous for broadening its utility in various tissue or cell types. In response to this need, vector pseudotyping, mosaic capsids, and targeting ligand insertion into the capsid have shown promise for altering AAV specificity. In addition, library selection and directed evolution have recently emerged as promising approaches to modulate AAV tropism despite limited knowledge of viral structure–function relationships. Second, pre-existing immunity to AAV must be addressed for successful clinical application of AAV vectors. “Shielding” polymers, site-directed mutagenesis, and alternative AAV serotypes have shown success in avoiding immune neutralization. Furthermore, directed evolution of the AAV capsid is a high throughput approach that has yielded vectors with substantial resistance to neutralizing antibodies. Molecular engineering and directed evolution of AAV vectors therefore offer promise for generating ‘designer’ gene delivery vectors with enhanced properties.
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