慢病毒基因治疗脑肾上腺脑白质营养不良。

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy.

机构信息

From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.) and Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School (C.N.D., D.A.W.), Boston, Bluebird Bio, Somerville (G.F.D., L.D., A.C.D., H.L.T.), and McNeil Pediatrics Consultancy, Sudbury (E.M.) - all in Massachusetts; the Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota (T.C.L., A.O.G., P.J.O.), and Midwest Radiology (D.J.L.) - both in Minneapolis; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (S.D.O., R.S., S.A.H.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., P.G.); INSERM, Université Paris-Saclay, Hôpital Kremlin-Bicêtre (P.A.), the Reference Center for Leukodystrophies, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay (C.S.), and Robert-Debre Hospital, GHU Nord-Université de Paris (J.-H.D.) - all in Paris; the Departments of Pediatric Oncology/Hematology/Hemostaseology (J.-S.K.) and Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases (U.P.), University Hospital Leipzig, Leipzig, Germany; Instituto Neurogenia and Hospital Universitario Austral - both in Buenos Aires (H.A.); Women's and Children's Health Network and the University of Adelaide - both in Adelaide, SA, Australia (N.S.); ITACI/Instituto da Criança-Hospital das Clínicas da Universidade de São Paulo, Sao Paulo (J.F.F.); and Shape Therapeutics, Seattle (A.C.D.).

出版信息

N Engl J Med. 2024 Oct 10;391(14):1302-1312. doi: 10.1056/NEJMoa2400442.

DOI:10.1056/NEJMoa2400442

PMID:39383459

Abstract

BACKGROUND

Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy.

METHODS

In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score.

RESULTS

A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up.

CONCLUSIONS

At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.).

摘要

背景

脑肾上腺脑白质营养不良是一种严重的 X 连锁肾上腺脑白质营养不良，其特征是白质疾病、丧失神经功能和早逝。Elivaldogene autotemcel（eli-cel）基因治疗由自体 CD34+细胞组成，通过含有 cDNA 的 Lenti-D 慢病毒载体转导，正在患有脑肾上腺脑白质营养不良的患者中进行测试。

方法

在一项 2-3 期研究中，我们评估了 eli-cel 治疗早期脑肾上腺脑白质营养不良且磁共振成像（MRI）显示有活跃炎症的男孩的疗效和安全性。主要疗效终点是 24 个月时无任何 6 种主要功能障碍的存活。次要终点包括 24 个月时的总生存率和从基线到 24 个月时总神经功能评分的变化。

结果

共有 32 名患者接受了 eli-cel 治疗；29 名患者（91%）完成了 24 个月的研究，并正在长期随访研究中进行监测。在 24 个月时，这 29 名患者均无主要功能障碍；总生存率为 94%。在最近的评估（中位随访 6 年）中，与基线评分相比，32 名患者中的 30 名（94%）的神经功能评分稳定；26 名患者（81%）无主要功能障碍。4 名患者发生与 eli-cel 直接相关的不良事件。1 名患者在 92 个月时出现骨髓增生异常综合征（MDS）伴过多前体细胞；该患者接受了同种异体造血干细胞移植，在最近的随访中没有 MDS。