Self-complementary AAV vectors; Advances and applications
Self-complementary AAV vectors; Advances and applications
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DOI：
10.1038/mt.2008.171
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发表时间：
2008-10-01
影响因子：
12.4
通讯作者：
McCarty, Douglas M.
中科院分区：
文献类型：
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作者：
McCarty, Douglas M.
大量的临床前研究已经证明了重组腺相关病毒(RAAV)基因递送载体的有效性，最近的临床试验也显示了良好的结果。然而，就转导所需的含有基因组的颗粒数量而言，这些载体的效率受到阻碍，因为在表达之前需要将单链DNA(SsDNA)基因组转换为双链DNA(DsDNA)。这一步骤可以通过使用自我互补载体来完全绕过，这种载体包装了一个反向重复基因组，可以折叠成dsDNA，而不需要DNA合成或多个载体基因组之间的碱基配对。这种效率的重要权衡是失去载体一半的编码能力，尽管小的蛋白质编码基因(高达55kd)和任何目前可用的基于RNA的疗法都是可以适应的。根据组织、细胞类型和给药途径的不同，自互补AAV(ScAAV)载体在效率上的提高从中等到惊人不等。除了自互补载体的构建和物理性质外，本文还将对肝脏、肌肉和中枢神经系统(CNS)等多种组织中不同反应的基础进行探讨。
Numerous preclinical studies have demonstrated the efficacy of recombinant adeno-associated virus (rAAV) gene delivery vectors, and recent clinical trials have shown promising results. However, the efficiency of these vectors, in terms of the number of genome-containing particles required for transduction, is hindered by the need to convert the single-stranded DNA (ssDNA) genome into double-stranded DNA (dsDNA) prior to expression. This step can be entirely circumvented through the use of self-complementary vectors, which package an inverted repeat genome that can fold into dsDNA without the requirement for DNA synthesis or base-pairing between multiple vector genomes. The important trade-off for this efficiency is the loss of half the coding capacity of the vector, though small protein-coding genes (up to 55 kd), and any currently available RNA-based therapy, can be accommodated. The increases in efficiency gained with self-complementary AAV (scAAV) vectors have ranged from modest to stunning, depending on the tissue, cell type, and route of administration. Along with the construction and physical properties of self-complementary vectors, the basis of the varying responses in multiple tissues including liver, muscle, and central nervous system (CNS) will be explored in this review.