The Role of Recombinant AAV in Precise Genome Editing.
The Role of Recombinant AAV in Precise Genome Editing.
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DOI：
10.3389/fgeed.2021.799722
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发表时间：
2021
影响因子：
--
通讯作者：
Chatterjee S
中科院分区：
文献类型：
--
作者：
Bijlani S;Pang KM;Sivanandam V;Singh A;Chatterjee S
自50年前发现以来，复制缺陷型、非致病性、几乎无处不在的单链腺相关病毒（AAV）变得越来越重要。它们独特的生命周期和病毒-细胞相互作用导致重组AAV作为理想的遗传医学工具的发展，这些工具已发展成为有效的商业化基因疗法。AAV的一个独特特性是它们精确编辑基因组的能力。与所有当前的基因组编辑平台相比，AAV专门利用高保真同源重组（HR）途径，并且不需要外源核酸酶来预先切割基因组DNA。总之，这导致高度精确的编辑结果，其保留基因组完整性而不在靶位点处掺入插入缺失突变或病毒序列，同时还消除了脱靶遗传毒性的可能性。发现干细胞衍生的AAV（AAVHSC）以高靶向准确性和高效率介导精确和有效的HR。AAVHSC编辑在体内有丝分裂后细胞和组织中有效地发生。此外，AAV还具有内在递送机制的优点。因此，这种独特的基因组编辑平台对于纠正疾病相关突变而不增加突变负担具有巨大的前景。本文将重点介绍直接AAV介导的基因组编辑的独特性质及其潜在的作用机制。
The replication-defective, non-pathogenic, nearly ubiquitous single-stranded adeno-associated viruses (AAVs) have gained importance since their discovery about 50 years ago. Their unique life cycle and virus-cell interactions have led to the development of recombinant AAVs as ideal genetic medicine tools that have evolved into effective commercialized gene therapies. A distinctive property of AAVs is their ability to edit the genome precisely. In contrast to all current genome editing platforms, AAV exclusively utilizes the high-fidelity homologous recombination (HR) pathway and does not require exogenous nucleases for prior cleavage of genomic DNA. Together, this leads to a highly precise editing outcome that preserves genomic integrity without incorporation of indel mutations or viral sequences at the target site while also obviating the possibility of off-target genotoxicity. The stem cell-derived AAV (AAVHSCs) were found to mediate precise and efficient HR with high on-target accuracy and at high efficiencies. AAVHSC editing occurs efficiently in post-mitotic cells and tissues in vivo. Additionally, AAV also has the advantage of an intrinsic delivery mechanism. Thus, this distinctive genome editing platform holds tremendous promise for the correction of disease-associated mutations without adding to the mutational burden. This review will focus on the unique properties of direct AAV-mediated genome editing and their potential mechanisms of action.
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