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

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

作　　者：Qiu-Hong Wang Jing Wanga Zhi-Pei Ling Zhi-Qiang Cui Jie Gong Rui Zhang Shi-Jun Li Yang-Yang Wang Rui Yang De-Hui Huang Wen He Jing Gao Chen Feng Pei-Li Hu Li-Ying Liu Lung-Ji Chang Li-Ping Zou 王秋红;王静;凌至培;崔志强;宫洁;章睿;李世俊;王杨阳;杨锐;黄德晖;何文;高敬;冯晨;胡沛丽;刘丽英;张隆基;邹丽萍

机构地区：[1]Senior Department of Pediatrics,Chinese PLA General Hospital,Beijing 100853,China [2]Medical School of Chinese PLA,Beijing 100853,China [3]Department of Neurosurgery,Hainan Hospital of PLA General Hospital,Sanya 572013,China [4]Department of Neurosurgery,The First Medical Center of Chinese PLA General Hospital,Beijing 100853,China [5]Chengdu Women’s and Children’s Central Hospital,School of Medicine,University of Electronic Science and Technology of China,Chengdu 611731,China [6]School of Medicine,University of Electronic Science and Technology of China,Chengdu 610054,China [7]Beijing Meikang Biotechnology Co.,LTD.,Beijing 100085,China [8]Department of Radiology,The First Medical Center of Chinese PLA General Hospital,Beijing 100853,China [9]Department of Neurology,The First Medical Center of Chinese PLA General Hospital,Beijing 100853,China [10]Department of Pediatrics,Xuanwu Hospital,Capital Medical University,Beijing 100053,China [11]Shenzhen Geno-Immune Medical Institute,Shenzhen 518057,China Beijing Institute for Brain Disorders [12]Center for Brain Disorders Research,Capital Medical University,Beijing 100069,China

出　　处：《Science Bulletin》2024年第16期2596-2603,共8页科学通报（英文版）

基　　金：supported by the Capital’s Funds for Health Improvement and Research(2022-1-5081);the National Key Research and Development Program of China(2023YFC2706304);Shenzhen Geno-Immune Medical Institute;Beijing Meikang Biotechnology Co.,LTD.

摘　　要：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 lL(vector titer:1×10^(9) transduction units per mL(TU/mL)),and the average dose per kilogram body weight ranges from 8 to 63.6 lL/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 injectionrelated 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 selflimited,or resolved within 3 d of symptomatic treatment.The maximal tolerable dose is 1600 lL.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).

关 键 词：ADRENOLEUKODYSTROPHY Lentiviral vectors ABCD1 Intracerebral injection 

分 类 号：R969.4[医药卫生—药理学]