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 to 1600 μL (vector titer: 1×109 transduction units per mL (TU/mL)), and the average dose per kilogram body weight ranges from 8 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 d 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).
摘要：
这是一只单臂，多中心，开放标签I期试验。将携带ABCD1基因（LV-ABCD1）的慢病毒载体（LV）直接注射到儿童脑肾上腺脑白质营养不良（CCALD）患者的大脑中，并进行多部位注射。注射剂量从200μL增加到1600μL（载体滴度：1×109TU/mL），每千克体重的平均剂量为8至63.6μL/kg。主要终点是安全性，剂量探索和免疫原性,次要终点是疗效和ABCD1蛋白表达的初步评估.共有7名患者参加了该I期研究，并随访了1年。无注射相关严重不良事件或死亡发生。与注射相关的常见不良事件是烦躁(71%，5/7）和发烧（37.2℃-38.5℃，57%,4/7）。不良事件是轻度和自限的，或在对症治疗3d内解决。最大耐受剂量为1600μL。5例（83.3%，5/6),未检测到慢病毒相关抗体。1年总生存率为100%。在中性粒细胞中检测到ABCD1蛋白的表达，单核细胞和淋巴细胞。这项研究表明，脑内注射LV-ABCD1用于CCALD是安全的，并且可以在体内成功实现LV转导；即使最大剂量也不会增加不良事件的风险。此外，直接注射LV-ABCD1显示低免疫原性.此外,脑内注射LV-ABCD1的有效性已得到初步证明,但仍需进一步研究.本研究已在中国临床试验注册中心(https://www.chictr.org.cn/,注册号:ChiCTR1900026649)。
