Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.
Viruses. 2010 Oct;2(10):2290-2355. doi: 10.3390/v2102290. Epub 2010 Oct 13.
Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and "bridging" interactions. "Bridging" interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of "bridging interactions" such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated "stealth" vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications.
实现高效、靶向的腺病毒载体基因传递是临床基因治疗领域的长期目标。为了实现这一目标，平台载体必须将有效的重新靶向策略与去靶向修饰相结合，以消除天然受体结合（即 CAR/整合素/硫酸乙酰肝素蛋白聚糖）和“桥接”相互作用。“桥接”相互作用是指凝血因子结合，即凝血因子 X（FX），它通过与表面表达的硫酸乙酰肝素蛋白聚糖（HSPG）结合，在体内介导肝细胞转导。这些相互作用可能导致 Ad5 在肝脏中的非靶向隔离及其特征性剂量限制的肝毒性，从而显著限制基于 Ad5 的治疗剂的体内靶向效率和临床潜力。迄今为止，已经描述了各种重新靶向腺病毒（Ad）的方法。这些方法包括遗传修饰策略，即在纤维突顶点结构域、纤维轴、五邻体基底、pIX 或六邻体中纳入肽配体，将衣壳蛋白假型化为包括全长纤维替代或纤维突顶点嵌合体，使用非人类 Ad 物种或来自其他病毒家族的衣壳蛋白进行假型化，六邻体高变区（HVR）替代以及针对表面表达的靶抗原的 scFv、生长因子或单克隆抗体的基于接头的缀合/交联。为了最大限度地重新靶向，可以同时采用允许从腺病毒衣壳与循环系统成分（如凝血因子、红细胞、预先存在的中和抗体）之间的不良相互作用中去靶向的策略。去靶向可以通过遗传消融天然受体结合决定簇、消融“桥接”相互作用（如 Ad5 的五邻体和凝血因子 X（FX）之间发生的相互作用）来实现，或者通过使用避免这些相互作用的聚合物涂层“隐形”载体来实现。通过组合多种遗传和/或化学修饰，可以实现同时重新靶向和去靶向。
