Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.
Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.
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DOI：
10.1056/nejmoa1700554
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发表时间：
2017-10-26
期刊：
影响因子：
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通讯作者：
Williams DA
中科院分区：
文献类型：
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作者：
Eichler F;Duncan C;Musolino PL;Orchard PJ;De Oliveira S;Thrasher AJ;Armant M;Dansereau C;Lund TC;Miller WP;Raymond GV;Sankar R;Shah AJ;Sevin C;Gaspar HB;Gissen P;Amartino H;Bratkovic D;Smith NJC;Paker AM;Shamir E;O'Meara T;Davidson D;Aubourg P;Williams DA
在X连锁肾上腺脑白质营养不良中，ABCD 1突变导致ALD蛋白功能丧失。脑肾上腺脑白质营养不良的特征是脱髓鞘和神经变性。导致神经功能丧失和死亡的疾病进展只能通过异基因造血干细胞移植来阻止。我们招募了患有脑肾上腺脑白质营养不良的男孩参加一项单组、开放标签、2-3期安全性和疗效研究。要求患者在筛选时具有早期疾病和磁共振成像（MRI）上的钆增强。研究治疗涉及输注用elivaldogene tavalentivec（Lenti-D）慢病毒载体转导的自体CD 34+细胞。在这项中期分析中，评估了患者的移植物抗宿主病、死亡和主要功能障碍的发生率，以及神经功能和MRI病变程度的变化。主要终点是在输注后24个月存活且无重大功能障碍。共有17名男孩接受了Lenti-D基因治疗。中期分析时，中位随访时间为29.4个月（范围：21.6 - 42.0）。所有患者在移植后都有基因标记的细胞，没有证据表明在已知癌基因附近有优先整合或克隆生长。在所有患者中观察到可测量的ALD蛋白。未报告治疗相关死亡或移植物抗宿主病; 17例患者中有15例（88%）存活，无重大功能障碍，临床症状轻微。一名神经功能迅速恶化的患者死于疾病进展。另一名患者在MRI上有疾病进展的证据，退出研究接受异基因干细胞移植，后来死于移植相关并发症。这项研究的早期结果表明，Lenti-D基因治疗可能是一种安全有效的替代异基因干细胞移植的男孩与早期脑肾上腺脑白质营养不良。需要额外的随访来充分评估反应持续时间和长期安全性。
In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2–3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety.