A 9-year-old boy with adrenoleukodystrophy due to ABCD1 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 ABCD1-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 ABCD1 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 ABCD1 gene product is of interest, and we postulate that it is related to the patient’s whole ABCD1 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 全基因缺失的脑肾上腺脑白质营养不良患者慢病毒载体基因治疗的继发性失败


一名 9 岁男孩因 ABCD1 全基因缺失而患有肾上腺脑白质营养不良，诊断为活动性脑肾上腺脑白质营养不良，其特征是脑部 MRI 显示脱髓鞘和钆增强。作为 ALD-104 临床试验的一部分，他接受了造血细胞移植 （HCT），使用表达 ABCD1 的慢病毒载体 （eli-cel [elivaldogene autotemcel]）转导的自体 CD34+ 细胞。HCT 后 50 天，患者的 MRI 显示钆消退;全血载体拷贝数 （VCN） 为 0.666 拷贝/mL。HCT 后 6 个月，MRI 显示钆增强再次出现;VCN 降至 0.029 拷贝/mL。移植后 9 个月可检测到针对 ABCD1 基因产物的多克隆抗体，显示对过氧化物酶体的反应性，表明存在免疫反应;然而，没有显示与人 CD34 + 细胞结合的抗体。患者在基因治疗后 12 个月成功接受了同种异体 HCT，导致钆消退、脑部疾病稳定和抗体消失。ABCD1 基因产物抗体的重合 VCN 丢失和外观值得关注，我们假设它与患者的整个 ABCD1 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因免疫反应而导致的基因治疗疗效损失。