1. Phase I clinical trial of intracerebral injection of lentiviral-ABCD1 for the treatment of cerebral adrenoleukodystrophy.
- Author
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Wang QH, Wang J, Ling ZP, Cui ZQ, Gong J, Zhang R, Li SJ, Wang YY, Yang R, Huang DH, He W, Gao J, Feng C, Hu PL, Liu LY, Chang LJ, and Zou LP
- Subjects
- Humans, Male, Child, Female, Adolescent, Child, Preschool, Brain metabolism, Brain pathology, Treatment Outcome, Adrenoleukodystrophy therapy, Adrenoleukodystrophy genetics, Lentivirus genetics, ATP Binding Cassette Transporter, Subfamily D, Member 1 genetics, Genetic Vectors administration & dosage, Genetic Therapy methods
- 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: 1×10
9 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)., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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