Engineering targeted viral vectors for gene therapy.
Engineering targeted viral vectors for gene therapy.
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DOI：
10.1038/nrg2141
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发表时间：
2007-08
期刊：
影响因子：
--
通讯作者：
Curiel DT
中科院分区：
文献类型：
--
作者：
Waehler R;Russell SJ;Curiel DT
将遗传疾病机制的知识转化为基因疗法的进程进展缓慢，临床成功有限。一个主要原因是转移载体（通常是病毒来源）没有充分靶向目标细胞。为了成功传递遗传物质，转导靶向通常对于进入靶细胞并避免非靶细胞转导产生的副作用至关重要。已经开发了许多将病毒载体靶向特定细胞的技术。它们可以分为三种类型：使用来自其他病毒的接头蛋白的系统（假型）；使用接头将靶向配体与载体偶联的系统；以及将靶向部分基因整合到病毒基因组中的系统。虽然涉及接头蛋白的系统在临床前评估中非常有用，但利用基因整合的靶向配体的系统对于临床应用来说是有利的。几种靶向原理的组合（包括自然趋向性、假型和接头的消除）和新颖的组合（例如噬菌体载体中的腺相关病毒（AAV）基因组）允许系统性载体应用。一项针对靶向逆转录病毒的初步临床研究表明，将实验室的成功转移到患者应用中是可行的，这强调了靶向载体不存在主要的监管障碍。通过使用转胞吞作用或细胞载体使载体在特定位点移出血管内皮，将促进全身载体应用。将现有靶向技术应用于新的病毒载体血清型和新的载体类别正在进一步扩展治疗能力。在血液中发现了载体全身应用的障碍，如针对载体的免疫反应以及血液蛋白与载体的结合。一些目标方法可能有可能绕过这些障碍。为了临床前评估新的靶向策略，可以使用几种不同程度反映人类情况的模型。原代细胞、组织切片系统和转基因动物的使用似乎特别有前途。成像技术提供了在不牺牲动物模型的情况下实时监测体内载体的能力。这些技术有助于载体靶向和生物分布研究。基因治疗的一个关键挑战是载体靶向特定细胞，同时避免对其他组织的影响。最近开发了几种策略来靶向主要病毒载体，使它们更接近临床应用。为了实现治疗成功，基因治疗的转移载体必须能够转导靶细胞，同时避免对非靶细胞的影响。尽管病毒载体的转导效率很高，但它们的向性常常不符合治疗需要。过去，由于缺乏适当的靶向，基因治疗的巨大潜力只能得到部分开发。使用多种技术修饰病毒载体取得了实质性进展，现在可以在体外靶向多种细胞类型。尽管体内应用仍然存在重要挑战，但针对靶向载体的首次临床试验已经开始进行。
Translating knowledge of genetic disease mechanisms into gene therapies has been slow with limited clinical success. One major reason is that the transfer vectors, which are most often of viral origin, are not targeted sufficiently towards the cells of interest. To achieve successful delivery of genetic material, transductional targeting is often essential to enter the target cell and to avoid side effects from the transduction of non-target cells. Many techniques to target viral vectors to specific cells have been developed. They can be divided into three types: systems that use adaptor proteins from other viruses (pseudotyping); systems that use adaptors to couple the targeting ligand to the vector; and systems that genetically incorporate the targeting moiety into the viral genome. Whereas systems involving adaptor proteins are highly useful in preclinical evaluations, systems that make use of genetically incorporated targeting ligands are advantageous for clinical applications. Combinations of several targeting principles (including ablation of natural tropism, pseudotyping and adaptors) and novel combinations (such as the adeno-associated virus (AAV) genome in a phage vector) allow systemic vector application. An initial clinical study with a targeted retrovirus showed feasibility to transfer laboratory success to patient application, underlining that there are no principal regulatory barriers for targeted vectors. Systemic vector applications will be facilitated by enabling the vector to move beyond the vascular endothelium at specific sites, using transcytosis or cellular vehicles. The application of existing targeting techniques to new viral vector serotypes and new vector classes is extending the therapeutic capabilities further. Obstacles to systemic application of vectors are found in the blood as immune reactions against the vector and as binding of blood proteins to the vector. Some targeting approaches might have the potential to circumvent these obstacles. To preclinically evaluate new targeting strategies, several models that reflect the human situation to varying degrees are available. The use of primary cells, tissue-slice systems and transgenic animals seems to be especially promising. Imaging technologies provide the ability to monitor the vector in vivo in real time without sacrificing the animal model. These techniques facilitate vector targeting and biodistribution studies. A key challenge in gene therapy is vector targeting to specific cells, while avoiding effects on other tissues. Several strategies have been developed recently to enable targeting of the main viral vectors, moving them a step closer to clinical use. To achieve therapeutic success, transfer vehicles for gene therapy must be capable of transducing target cells while avoiding impact on non-target cells. Despite the high transduction efficiency of viral vectors, their tropism frequently does not match the therapeutic need. In the past, this lack of appropriate targeting allowed only partial exploitation of the great potential of gene therapy. Substantial progress in modifying viral vectors using diverse techniques now allows targeting to many cell types in vitro. Although important challenges remain for in vivo applications, the first clinical trials with targeted vectors have already begun to take place.
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