Robbins P D, Ghivizzani S C
Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, PA 15261, USA.
Pharmacol Ther. 1998 Oct;80(1):35-47.
Viruses have evolved to become highly efficient at nucleic acid delivery to specific cell types while avoiding immunosurveillance by an infected host. These properties make viruses attractive gene-delivery vehicles, or vectors, for gene therapy. Several types of viruses, including retrovirus, adenovirus, adeno-associated virus (AAV), and herpes simplex virus, have been modified in the laboratory for use in gene therapy applications. Because these vector systems have unique advantages and limitations, each has applications for which it is best suited. Retroviral vectors can permanently integrate into the genome of the infected cell, but require mitotic cell division for transduction. Adenoviral vectors can efficiently deliver genes to a wide variety of dividing and nondividing cell types, but immune elimination of infected cells often limits gene expression in vivo. Herpes simplex virus can deliver large amounts of exogenous DNA; however, cytotoxicity and maintenance of transgene expression remain as obstacles. AAV also infects many nondividing and dividing cell types, but has a limited DNA capacity. Alternatively, chimeric viral-vector systems that combine advantageous properties of two or more viral systems are also being explored. Although viral-mediated gene delivery has proved to be the most efficient means of gene transfer, nonviral means are also under development. Many of these nonviral systems incorporate portions of viral vectors to increase the efficiency of gene delivery or expression. Retrovirus, adenovirus, and AAV vectors are being evaluated currently in several Phase 1 clinical trials for treatment of diseases such as cancer, cystic fibrosis, Gaucher disease, and arthritis.
病毒已经进化到能够高效地将核酸递送至特定细胞类型，同时避免被感染宿主的免疫监视。这些特性使病毒成为基因治疗中颇具吸引力的基因递送载体，即载体。包括逆转录病毒、腺病毒、腺相关病毒（AAV）和单纯疱疹病毒在内的几种病毒已在实验室中进行改造，用于基因治疗应用。由于这些载体系统具有独特的优势和局限性，每种都有其最适合的应用。逆转录病毒载体可以永久整合到受感染细胞的基因组中，但转导需要有丝分裂细胞分裂。腺病毒载体可以有效地将基因递送至多种分裂和非分裂细胞类型，但受感染细胞的免疫清除常常限制体内的基因表达。单纯疱疹病毒可以递送大量外源DNA；然而，细胞毒性和转基因表达的维持仍然是障碍。AAV也感染许多非分裂和分裂细胞类型，但DNA容量有限。此外，结合两种或更多病毒系统优势特性的嵌合病毒载体系统也在探索中。尽管病毒介导的基因递送已被证明是最有效的基因转移手段，但非病毒手段也在开发中。许多这些非病毒系统都包含病毒载体的部分成分，以提高基因递送或表达的效率。逆转录病毒、腺病毒和AAV载体目前正在多项1期临床试验中接受评估，用于治疗癌症、囊性纤维化、戈谢病和关节炎等疾病。
