Eichler Florian, Duncan Christine, Musolino Patricia L, Orchard Paul J, De Oliveira Satiro, Thrasher Adrian J, Armant Myriam, Dansereau Colleen, Lund Troy C, Miller Weston P, Raymond Gerald V, Sankar Raman, Shah Ami J, Sevin Caroline, Gaspar H Bobby, Gissen Paul, Amartino Hernan, Bratkovic Drago, Smith Nicholas J C, Paker Asif M, Shamir Esther, O'Meara Tara, Davidson David, Aubourg Patrick, Williams David A
From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.), Dana-Farber and Boston Children's Cancer and Blood Disorders Center (C. Duncan, M.A., C. Dansereau, D.A.W.), and Boston Children's Hospital, Harvard Medical School, and Harvard Stem-Cell Institute (D.A.W.), Boston, and Bluebird Bio, Cambridge (A.M.P., E.S., T.O., D.D.) - all in Massachusetts; University of Minnesota Children's Hospital, Minneapolis (P.J.O., T.C.L., W.P.M., G.V.R.); University of California, Los Angeles, Los Angeles (S.D.O., R.S., A.J.S.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., H.B.G., P.G.); Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France (C.S., P.A.); Fundacion Investigar, Buenos Aires (H.A.); and Women's and Children's Hospital, North Adelaide, SA, Australia (D.B., N.J.C.S.).
N Engl J Med. 2017 Oct 26;377(17):1630-1638. doi: 10.1056/NEJMoa1700554. Epub 2017 Oct 4.
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. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
在X连锁肾上腺脑白质营养不良中，ABCD1基因突变导致肾上腺脑白质营养不良蛋白功能丧失。脑型肾上腺脑白质营养不良的特征是脱髓鞘和神经变性。只有通过异基因造血干细胞移植才能阻止导致神经功能丧失和死亡的疾病进展。
我们将患有脑型肾上腺脑白质营养不良的男孩纳入一项单组、开放标签的2-3期安全性和有效性研究。患者在筛查时需患有早期疾病且磁共振成像（MRI）有钆增强表现。研究性治疗包括输注用elivaldogene tavalentivec（Lenti-D）慢病毒载体转导的自体CD34+细胞。在本次中期分析中，评估患者移植物抗宿主病、死亡和主要功能残疾的发生情况，以及神经功能和MRI上病变范围的变化。主要终点是输注后24个月时存活且无主要功能残疾。
共有17名男孩接受了Lenti-D基因治疗。在中期分析时，中位随访时间为29.4个月（范围为21.6至42.0个月）。所有患者移植后均有基因标记细胞，没有证据表明在已知致癌基因附近有优先整合或克隆性增殖。在所有患者中均观察到可测量的肾上腺脑白质营养不良蛋白。未报告与治疗相关的死亡或移植物抗宿主病；17名患者中有15名（88%）存活且无主要功能残疾，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MRI有疾病进展证据的患者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。
本研究的早期结果表明，对于患有早期脑型肾上腺脑白质营养不良的男孩，Lenti-D基因治疗可能是异基因干细胞移植的一种安全有效的替代方法。需要进一步随访以全面评估反应持续时间和长期安全性。（由蓝鸟生物公司等资助；STARBEAM临床试验注册号，NCT01896102；欧洲临床试验注册编号，2011-001953-10。）
