Tropism-modification strategies for targeted gene delivery using adenoviral vectors.
Tropism-modification strategies for targeted gene delivery using adenoviral vectors.
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DOI：
10.3390/v2102290
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Baker AH
中科院分区：
文献类型：
--
作者：
Coughlan L;Alba R;Parker AL;Bradshaw AC;McNeish IA;Nicklin SA;Baker AH
用腺病毒载体实现高效、靶向的基因传递是临床基因治疗领域长期追求的目标。为了实现这一点，平台载体必须将有效的重定向策略与去靶向修饰结合起来，以消除天然受体结合(即CAR/整合素/硫酸乙酰肝素蛋白多糖)和“桥接”相互作用。“桥接”作用是指凝血因子结合，即凝血因子X(FX)，通过与表面表达的硫酸乙酰肝素蛋白多糖(HSPGs)结合，在体内连接肝细胞转导的桥梁。这些相互作用可能导致Ad5在肝脏中的靶外滞留及其特有的剂量限制性肝毒性，从而显著限制基于Ad5的治疗的体内靶向效率和临床潜力。到目前为止，已经描述了重定向腺病毒(Ad)的各种方法。这些策略包括结合多肽配体的基因修饰策略(在纤维结节结构域、纤维轴、五元碱基、Pix或六角体内)、衣壳蛋白的伪分型以包括全纤维替代或纤维节嵌合体、与非人类Ad物种或来自其他病毒家族的衣壳蛋白的伪分型、六邻体高变区(HVR)替换以及针对表面表达的靶抗原的单链抗体、生长因子或单抗的基于接头的连接/交联。为了最大限度地重定向，可以同时使用允许去靶向的策略，这些策略允许从Ad衣壳和循环系统组件(例如，凝血因子、红细胞、先前存在的中和抗体)之间的不良相互作用中去靶。脱靶可以通过基因消融天然的受体结合决定因素，消融发生在Ad5的六邻体和凝血因子X(FX)之间的“桥接作用”来实现，或者通过使用避免这些作用的聚合物包被的“隐形”载体来实现。可以通过组合多种遗传和/或化学修饰来实现同时的重定向和去靶向。
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.
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