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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.)

Background: Addison's disease and X-linked adrenoleukodystrophy (X-ALD) (Addison's-only) are two diseases that need to be identified. Addison's disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison's-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison's disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD., Methods: We retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics., Results: Two patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison's disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109_110insGCCA (p.C39Pfs*156), c.1394-2 A > C (NM_000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison's-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum., Conclusions: Patients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison's disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison's-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy., (© 2024. The Author(s).)

Background: Coronavirus disease 2019 (COVID-19) can not only infect the respiratory system but also affect the nervous system through the release of inflammatory factors. Our study aimed to investigate the effect of COVID-19 infection on cerebral adrenoleukodystrophy (ALD)., Methods: Changes in the neurological symptoms of cerebral ALD after infection with COVID-19 from January 2022 to February 2023 were retrospectively analyzed. The primary assessment indicator was the Neurologic Function Scale (NFS) score., Results: A total of 17 male patients with cerebral ALD were enrolled, with a median age of 101 months (80 to 151 months). Among them, 11 (11 of 17, 64.7%) developed an exacerbation of neurological symptoms after COVID-19 infection. Two patients with NFS = 0 started presenting with neurological symptoms after infection. Fifteen patients were in the advanced stage (NFS >1 and/or Loes score >9), of which nine did not progress to major functional disabilities (MFDs). Seven of the nine patients (77.8%) experienced an increase in NFS scores, ranging from 1 to 9 points, within two weeks of COVID-19 infection, with four of them experiencing MFDs. For the other six patients who had progressed to MFDs, there was not much room for further degeneration, so the NFS score did not increase after COVID-19 infection. No deaths related to COVID-19 infection occurred., Conclusions: COVID-19 infection may aggravate neurological symptoms of cerebral ALD, particularly among patients who have not yet progressed to MFDs. Therefore, COVID-19 may accelerate the course of cerebral ALD, so protecting patients from infection is essential for maintaining the stability of the disease., Competing Interests: Declaration of competing interest The authors declare that there are no commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

X-linked adrenoleukodystrophy (ALD) is a rare peroxisome disease with phenotypic heterogeneity. There is a lack of suitable in vitro models to study its pathogenesis. We established two strains of iPSCs from skin fibroblasts of patients with childhood cerebral ALD and Addison's disease, respectively. CytoTune™2.0 Sendai reprogramming kit was used. The iPSC lines showed typical stem cell morphology, normal karyotype, and carrying ABCD1 variation. The iPSC lines express pluripotency markers, and have the capacity to differentiate into three germ layers. iPSCs can be used as an alternative cell source for ALD in vitro model to study its pathogenesis and therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)