Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
Department of Pediatrics, Michigan State University, East Lansing, MI 48824, USA.
Viruses. 2010 Sep;2(9):2013-2036. doi: 10.3390/v2092013. Epub 2010 Sep 24.
Adenovirus (Ad) based gene transfer vectors continue to be the platform of choice for an increasing number of clinical trials worldwide. In fact, within the last five years, the number of clinical trials that utilize Ad based vectors has doubled, indicating growing enthusiasm for the numerous positive characteristics of this gene transfer platform. For example, Ad vectors can be easily and relatively inexpensively produced to high titers in a cGMP compliant manner, can be stably stored and transported, and have a broad applicability for a wide range of clinical conditions, including both gene therapy and vaccine applications. Ad vector based gene transfer will become more useful as strategies to counteract innate and/or pre-existing adaptive immune responses to Ads are developed and confirmed to be efficacious. The approaches attempting to overcome these limitations can be divided into two broad categories: pre-emptive immune modulation of the host, and selective modification of the Ad vector itself. The first category of methods includes the use of immunosuppressive drugs or specific compounds to block important immune pathways, which are known to be induced by Ads. The second category comprises several innovative strategies inclusive of: (1) Ad-capsid-display of specific inhibitors or ligands; (2) covalent modifications of the entire Ad vector capsid moiety; (3) the use of tissue specific promoters and local administration routes; (4) the use of genome modified Ads; and (5) the development of chimeric or alternative serotype Ads. This review article will focus on both the promise and the limitations of each of these immune evasion strategies, and in the process delineate future directions in developing safer and more efficacious Ad-based gene transfer strategies.
腺病毒（Ad）为基础的基因转移载体继续成为全球越来越多临床试验的首选平台。事实上，在过去五年中，利用 Ad 为基础的载体进行临床试验的数量增加了一倍，这表明人们对这种基因转移平台的许多积极特性越来越感兴趣。例如，Ad 载体可以很容易地以符合 cGMP 的方式大量生产，具有较高的效价，可以稳定地储存和运输，并且具有广泛的适用性，适用于广泛的临床情况，包括基因治疗和疫苗应用。随着对抗 Ad 固有和/或预先存在的适应性免疫反应的策略的开发和证实有效，Ad 载体为基础的基因转移将变得更加有用。试图克服这些限制的方法可以分为两大类：抢先调节宿主的免疫，以及选择性修饰 Ad 载体本身。第一类方法包括使用免疫抑制剂或特定化合物来阻断已知由 Ads 诱导的重要免疫途径。第二类包括几种创新策略，包括：（1）Ad 衣壳展示特定的抑制剂或配体；（2）整个 Ad 载体衣壳部分的共价修饰；（3）使用组织特异性启动子和局部给药途径；（4）使用基因组修饰的 Ads；和（5）开发嵌合或替代血清型 Ads。这篇综述文章将重点讨论这些免疫逃避策略的前景和局限性，并在此过程中描绘出开发更安全、更有效的 Ad 为基础的基因转移策略的未来方向。
