Lentiviral gene therapy for X-linked chronic granulomatous disease
Lentiviral gene therapy for X-linked chronic granulomatous disease
复制标题
DOI：
10.1038/s41591-019-0735-5
复制
发表时间：
2020-01-27
期刊：
影响因子：
82.9
通讯作者：
Thrasher, Adrian J.
中科院分区：
文献类型：
--
作者：
Kohn, Donald B.;Booth, Claire;Thrasher, Adrian J.
慢性肉芽肿病（CGD）是一种罕见的吞噬细胞遗传性疾病（1，2）。我们报告了9例严重受累的X连锁CGD（X-CGD）患者的初步结果，这些患者在首次人体研究中接受了清髓性预处理后，接受了基于离体自体CD 34（+）造血干细胞和祖细胞的慢病毒基因治疗（试验注册号：NCT 02234934和NCT 01855685）。主要目的是评估12个月时植入细胞后代中生化和功能重建的安全性并评价其疗效和稳定性。次要目的包括评价对细菌和真菌感染的增强免疫力，以及评估造血干细胞转导和植入。2例入组患者在治疗3个月内死于既存合并症。在12个月时，7名存活患者中有6名表现出稳定的载体拷贝数（每个中性粒细胞0.4-1.8个拷贝）和16-46%氧化酶阳性中性粒细胞的持久性。没有克隆失调或转基因沉默的分子证据。存活的患者没有发生新的CGD相关感染，6名患者能够停止CGD相关的抗生素预防。在12个月的随访中，9例患者中有6例达到了主要目的，这表明自体基因治疗是CGD患者的一种有前途的方法。I/II期慢病毒基因治疗试验的初步结果提供了早期证据，支持其治疗X连锁慢性肉芽肿病患者的安全性和有效性。
Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells(1,2). We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34(+) hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients.Initial results from phase I/II lentiviral gene therapy trials provide early evidence supporting its safety and efficacy in treating patients with X-linked chronic granulomatous disease.