A 9-year-old boy with adrenoleukodystrophy due to whole-gene deletion was diagnosed with active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hematopoietic cell transplant (HCT) with autologous CD34 cells transduced with an -expressing lentiviral vector (eli-cel [elivaldogene autotemcel]) as part of the ALD-104 clinical trial. Fifty days after HCT, the patient’s MRI showed gadolinium resolution; the whole-blood vector copy number (VCN) was 0.666 copies/mL. Six months following HCT, an MRI showed re-emergence of gadolinium enhancement; the VCN had decreased to 0.029 copies/mL. Polyclonal antibodies to the gene product were detectable 9 months after transplant, showing reactivity to peroxisomes, suggesting an immune response; however, no antibody binding to human CD34 cells could be shown. The patient underwent a successful allogeneic HCT 12 months after gene therapy with resultant gadolinium resolution, cerebral disease stabilization, and the disappearance of antibodies. The coincident VCN loss and appearance of antibody to the gene product is of interest, and we postulate that it is related to the patient’s whole gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy.

中文翻译：

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ABCD1全基因缺失的脑性肾上腺脑白质营养不良患者慢病毒载体基因治疗二次失败


一名因全基因缺失而患有肾上腺脑白质营养不良的 9 岁男孩被诊断​​为活动性脑肾上腺脑白质营养不良，其特征是脑部 MRI 脱髓鞘和钆增强。作为 ALD-104 临床试验的一部分，他接受了用表达慢病毒载体 (eli-cel [elivaldogene autotemcel]) 转导的自体 CD34 细胞进行造血细胞移植 (HCT)。 HCT 后 50 天，患者的 MRI 显示钆分辨率；全血载体拷贝数（VCN）为0.666拷贝/mL。 HCT 六个月后，MRI 显示再次出现钆增强； VCN 已降至 0.029 拷贝/mL。移植后 9 个月可检测到针对该基因产物的多克隆抗体，显示出对过氧化物酶体的反应性，表明存在免疫反应；然而，没有显示出抗体与人 CD34 细胞结合。基因治疗 12 个月后，该患者成功接受了同种异体 HCT，结果是钆溶解、脑疾病稳定和抗体消失。 VCN 丢失和基因产物抗体同时出现很有趣，我们推测这与患者的整个基因缺失有关。我们建议密切监测正在考虑基因治疗的完全缺失患者由于免疫反应而导致的基因治疗功效丧失。