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

Qiu-Hong Wang ¹Jing Wang ²Zhi-Pei Ling ³Zhi-Qiang Cui ⁴Jie Gong ⁵Rui Zhang ⁶Shi-Jun Li ⁷Yang-Yang Wang ²Rui Yang ⁸De-Hui Huang ⁹Wen He ²Jing Gao ²Chen Feng ²Pei-Li Hu ²Li-Ying Liu ¹⁰Lung-Ji Chang ¹¹Li-Ping Zou¹²

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作者信息

1. Senior Department of Pediatrics,Chinese PLA General Hospital,Beijing 100853,China;Medical School of Chinese PLA,Beijing 100853,China
2. Senior Department of Pediatrics,Chinese PLA General Hospital,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;School of Medicine,University of Electronic Science and Technology of China,Chengdu 610054,China
6. Beijing Meikang Biotechnology Co.,LTD.,Beijing 100085,China
7. Department of Radiology,The First Medical Center of Chinese PLA General Hospital,Beijing 100853,China
8. School of Medicine,University of Electronic Science and Technology of China,Chengdu 610054,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. School of Medicine,University of Electronic Science and Technology of China,Chengdu 610054,China;Shenzhen Geno-Immune Medical Institute,Shenzhen 518057,China
12. Senior Department of Pediatrics,Chinese PLA General Hospital,Beijing 100853,China;Medical School of Chinese PLA,Beijing 100853,China;Beijing Institute for Brain Disorders,Center for Brain Disorders Research,Capital Medical University,Beijing 100069,China
折叠

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 adrenoleukodys-trophy(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 immuno-genicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 pro-tein.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 intracere-bral 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).

Key words

Adrenoleukodystrophy/Lentiviral vectors/ABCD1/Intracerebral injection

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基金项目

Capital's Funds for Health Improvement and Research(2022-1-5081)

National Key Research and Development Program of China(2023YFC2706304)

Shenzhen Geno-Immune Medical Institute,and Beijing Meikang Biotechnology Co.,LTD()

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

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