首都医科大学邹丽萍等研究人员合作完成脑内注射慢病毒-ABCD1治疗脑型肾上腺脑白质营养不良的I期临床试验。相关论文于2024年7月4日在线发表在《科学通报》杂志上。

研究人员报道了一项单臂、多中心、开放标签的I期临床试验。携带ABCD1基因的慢病毒载体（LV-ABCD1）被直接注射到患有脑型肾上腺脑白质营养不良（CCALD）患者的大脑中，并进行了多点注射。注射剂量从200 μL增加到1600 μL（载体滴度：1×10^9 TU/mL），平均剂量范围为每公斤体重8 μL至63.6 μL。主要终点是安全性、剂量探索和免疫原性，次要终点是初步评估疗效和ABCD1蛋白的表达。

共有7名患者参与了这项I期研究，并进行了为期1年的随访。未发生与注射相关的严重不良事件或死亡。与注射相关的常见不良事件是易怒（71%，5/7）和发热（37.2–38.5℃，57%，4/7）。不良事件均为轻度且自限性，或在对症治疗3天内消失。最大耐受剂量为1600 μL。在5例患者中（83.3%，5/6），未检测到与慢病毒相关的抗体。1年时的总体生存率为100%。在中性粒细胞、单核细胞和淋巴细胞中检测到了ABCD1蛋白的表达。

该研究表明，LV-ABCD1的脑内注射对于CCALD是安全的，并且可以在体内实现成功的慢病毒转导；即使是最大剂量也不会增加不良事件的风险。此外，直接注射LV-ABCD1显示出低免疫原性。此外，脑内注射LV-ABCD1的有效性已初步显现，但需要进一步研究。该研究已在中国临床试验注册中心注册（https://www.chictr.org.cn/，注册号：ChiCTR1900026649）。

附：英文原文

Title: Phase I clinical trial of intracerebral injection of lentiviral-ABCD1 for the treatment of cerebral adrenoleukodystrophy

Author: Lung-Ji Chang f k, Li-Ping Zou a b l

Issue&Volume: 2024/07/04

Abstract: This was a single-arm, multicenter, open-label phase I trial. Lentiviral vectors (LV) carrying the ABCD1 gene (LV-ABCD1) was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy (CCALD), and multi-site injection was performed. The injection dose increased from 200 μL to 1600 μL (vector titer: 1×109 TU/mL), and the average dose per kilogram body weight ranges from 8 μL/kg to 63.6 μL/kg. The primary endpoint was safety, dose‐exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein. A total of 7 patients participated in this phase I study and were followed for 1 year. No injection-related serious adverse event or death occurred. Common adverse events associated with the injection were irritability (71%, 5/7) and fever (37.2–38.5 ℃, 57%, 4/7). Adverse events were mild and self-limited, or resolved within 3 days of symptomatic treatment. The maximal tolerable dose is 1600 μL. In 5 cases (83.3%, 5/6), no lentivirus associated antibodies were detected. The overall survival at 1-year was 100%. The ABCD1 protein expression was detected in neutrophils, monocytes and lymphocytes. This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo; even the maximal dose did not increase the risk of adverse events. Furthermore, the direct LV-ABCD1 injection displayed low immunogenicity. In addition, the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed. This study has been registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/, registration number: ChiCTR1900026649).

DOI: 10.1016/j.scib.2024.04.072

Source: https://www.sciencedirect.com/science/article/abs/pii/S2095927324004778