Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia
Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia
复制标题
DOI：
10.1056/nejmoa1705342
复制
发表时间：
2018-04-19
影响因子：
158.5
通讯作者：
Cavazzana, M.
中科院分区：
文献类型：
--
作者：
Thompson, A. A.;Walters, M. C.;Cavazzana, M.
背景供体可用性和移植相关风险限制了同种异体造血细胞移植在输血依赖性β-地中海贫血患者中的广泛使用。在先前确定标记的 β-珠蛋白 (β(A-T87Q)) 基因的慢病毒转移可以替代 β-地中海贫血患者的长期红细胞输血后，我们希望评估这种基因疗法在输血依赖性 β-地中海贫血患者中的安全性和有效性。 方法 在两项 1-2 期研究中，我们从 22 名患者（12 至 35 年的血统）中获得了动员的自体 CD34+ 细胞。年龄）患有输血依赖性β-地中海贫血，并用 LentiGlobin BB305 载体离体转导细胞，该载体编码具有 T87Q 氨基酸取代的成人血红蛋白 (HbA) (HbA(T87Q))。在患者接受清髓性白消安调理后，将细胞重新输注。我们随后监测了不良事件、载体整合和具有复制能力的慢病毒水平。疗效评估包括总血红蛋白和 HbA(T87Q) 水平、输血要求和平均载体拷贝数。 结果 在输注基因修饰细胞后中位 26 个月（范围为 15 至 42）时，13 名非 β(0)/β(0) 基因型患者中除 1 名外均已停止接受红细胞输注； HbA(T87Q) 水平为 3.4 至 10.0 克/分升，总血红蛋白水平为 8.2 至 13.7 克/分升。在血红蛋白水平接近正常范围的受评估患者中实现了红细胞生成障碍生物标志物的校正。在 9 名具有 beta(0)/beta(0) 基因型或两个 IVS1-110 突变拷贝的患者中，年化输血量中位数减少了 73%，其中 3 名患者停止了红细胞输注。与治疗相关的不良事件是与自体干细胞移植相关的典型不良事件。未观察到与载体整合相关的克隆优势。 结论 使用 BB305 载体转导的自体 CD34+ 细胞进行基因治疗，减少或消除了 22 名严重 β 地中海贫血患者的长期红细胞输注需求，且未出现与药品相关的严重不良事件。 （由 Bluebird Bio 等资助；HGB-204 和 HGB-205 临床试验。政府编号：NCT01745120 和 NCT02151526。）
BACKGROUNDDonor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent beta-thalassemia. After previously establishing that lentiviral transfer of a marked beta-globin (beta(A-T87Q)) gene could substitute for long-term red-cell transfusions in a patient with beta-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent beta-thalassemia.METHODSIn two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent beta-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA(T87Q)). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbA(T87Q), transfusion requirements, and average vector copy number.RESULTSAt a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-beta(0)/beta(0) genotype had stopped receiving red-cell transfusions; the levels of HbA(T87Q) ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a beta(0)/beta(0) genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed.CONCLUSIONSGene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe beta-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials. gov numbers, NCT01745120 and NCT02151526.)