Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47^phox-deficient CGD (p47^phoxCGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34⁺ cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34⁺ cells derived from a p47^phoxCGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47^phoxCGD.

中文翻译：

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p47phox 缺陷型慢性肉芽肿病新型慢病毒基因疗法的临床前优化和安全性研究

慢性肉芽肿病 (CGD) 是一种吞噬细胞的遗传性血液病，使患者容易感染和发炎。最近一项针对最常见形式的 CGD（X 连锁）的慢病毒基因治疗临床试验表明，随着时间的推移，校正效果稳定，没有与基因治疗程序相关的不良事件。我们最近开发了一种用于 p47 ^phox缺陷型 CGD 的平行慢病毒载体（p47 ^phoxCGD），这种疾病的第二个最常见的形式。使用此载体，我们在该疾病的小鼠模型中观察到了 CGD 的生化校正。在准备临床试验批准时，我们按照良好实验室规范 (GLP) 原则进行了标准化的临床前研究，以评估基因治疗程序的安全性。我们报告在用慢病毒载体转导的人类造血干细胞中没有不良事件的证据，包括诱变和肿瘤发生。转导的人 CD34 ⁺细胞的生物分布研究表明，干细胞的归巢特性或植入能力没有受到负面影响。来自 p47 ^phox的CD34 ^+细胞CGD 患者接受优化的转导方案并移植到免疫功能低下的小鼠中。手术后，源自患者的中性粒细胞恢复了功能，表明基因校正成功。^{这些研究为慢病毒基因疗法治疗 p47 phox} CGD的首次人体临床试验铺平了道路。