Wang Cathy X, Cannon Paula M
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA.
Blood. 2016 May 26;127(21):2546-52. doi: 10.1182/blood-2016-01-678144. Epub 2016 Apr 6.
HIV/AIDS has long been at the forefront of the development of gene- and cell-based therapies. Although conventional gene therapy approaches typically involve the addition of anti-HIV genes to cells using semirandomly integrating viral vectors, newer genome editing technologies based on engineered nucleases are now allowing more precise genetic manipulations. The possible outcomes of genome editing include gene disruption, which has been most notably applied to the CCR5 coreceptor gene, or the introduction of small mutations or larger whole gene cassette insertions at a targeted locus. Disruption of CCR5 using zinc finger nucleases was the first-in-human application of genome editing and remains the most clinically advanced platform, with 7 completed or ongoing clinical trials in T cells and hematopoietic stem/progenitor cells (HSPCs). Here we review the laboratory and clinical findings of CCR5 editing in T cells and HSPCs for HIV therapy and summarize other promising genome editing approaches for future clinical development. In particular, recent advances in the delivery of genome editing reagents and the demonstration of highly efficient homology-directed editing in both T cells and HSPCs are expected to spur the development of even more sophisticated applications of this technology for HIV therapy.
长期以来，人类免疫缺陷病毒/获得性免疫缺陷综合征（HIV/AIDS）一直处于基因和细胞疗法发展的前沿。尽管传统的基因治疗方法通常涉及使用半随机整合的病毒载体将抗HIV基因添加到细胞中，但基于工程核酸酶的新型基因组编辑技术现在允许进行更精确的基因操作。基因组编辑的可能结果包括基因破坏，这在CCR5共受体基因上得到了最显著的应用，或者在目标位点引入小突变或更大的全基因盒插入。使用锌指核酸酶破坏CCR5是基因组编辑在人体中的首次应用，并且仍然是临床上最先进的平台，在T细胞和造血干/祖细胞（HSPCs）中有7项已完成或正在进行的临床试验。在此，我们综述了T细胞和HSPCs中CCR5编辑用于HIV治疗的实验室和临床研究结果，并总结了其他有前景的基因组编辑方法以供未来临床开发。特别是，基因组编辑试剂递送方面的最新进展以及在T细胞和HSPCs中高效同源定向编辑的证明，有望推动该技术在HIV治疗中更复杂应用的发展。
