Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV.
Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV.
复制标题
DOI：
10.1056/nejmoa1300662
复制
发表时间：
2014-03-06
期刊：
影响因子：
--
通讯作者：
June CH
中科院分区：
文献类型：
--
作者：
Tebas P;Stein D;Tang WW;Frank I;Wang SQ;Lee G;Spratt SK;Surosky RT;Giedlin MA;Nichol G;Holmes MC;Gregory PD;Ando DG;Kalos M;Collman RG;Binder-Scholl G;Plesa G;Hwang WT;Levine BL;June CH
CCR5是人类免疫缺陷病毒(HIV)的主要辅助受体。我们调查了基因的定点修饰(“基因编辑”)--在这种情况下，注入CCR5基因被锌指核酸酶(ZFN)永久失活的自体CD4T细胞--是否安全。我们招募了12名患者参加了一项开放标记、非随机、非对照的单剂量ZFN修饰的自体CD4T细胞研究。这些患者在接受高效抗逆转录病毒治疗的同时，患有慢性无核型艾滋病毒感染。其中6人在输注100亿个自体CD4T细胞4周后中断了抗逆转录病毒治疗，其中11%到28%是用ZFN转基因的。根据与治疗相关的不良事件评估，主要结果是安全性。次要结果包括免疫重建和艾滋病毒抵抗力的措施。一个严重的不良事件与输注ZFN修饰的自体CD4T细胞有关，并被归因于输血反应。在第一周，CD4T细胞计数的中位数为每立方毫米1517个，比输液前的每立方毫米448个显著增加(P<；0.001)。CCR5修饰的CD4T细胞在1周的中位浓度为每立方毫米250个细胞。这占循环外周血单核细胞的8.8%和循环CD4T细胞的13.9%。改良细胞的平均半衰期估计为48周。在治疗中断和由此导致的病毒血症期间，循环中CCR5修饰细胞的下降(−1.81个/天)显著低于未修饰的细胞(−7.25个/天)(P=0.02)。在可以进行评估的四名患者中，有一名患者的艾滋病毒RNA检测不到。大多数患者的血液中HIV DNA水平下降。在本研究范围内，CCR5修饰的自体CD4T细胞输注是安全的。(由国家过敏和传染病研究所等资助；ClinicalTrials.gov编号，NCT00842634。)
CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene (“gene editing”) — in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN) — is safe. We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance. One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P<0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (−1.81 cells per day) was significantly less than the decline in unmodified cells (−7.25 cells per day) (P = 0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients. CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.)