Background

Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia. After previously establishing that lentiviral transfer of a marked β-globin (βA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent β-thalassemia.

Methods

In two phase 1–2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent β-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). 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 HbAT87Q, transfusion requirements, and average vector copy number.

Results

At 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–β0/β0 genotype had stopped receiving red-cell transfusions; the levels of HbAT87Q 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 β0/β0 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.

Conclusions

Gene 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 β-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.)

FREE QUICK TAKE VIDEO SUMMARY
LentiGlobin Gene Therapy for β-Thalassemia
 02:03

中文翻译：

---

输血依赖型β地中海贫血患者的基因治疗

背景

供体的可用性和与移植相关的风险限制了异基因造血细胞移植在依赖输血的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（βA-T87Q）基因的慢病毒转移可以代替β地中海贫血患者的长期红细胞输注后，我们希望评估这种基因疗法在患者中的安全性和有效性输血依赖型β地中海贫血。

方法

在两项1至2期研究中，我们从22位年龄在12至35岁之间的输血依赖性β地中海贫血患者中获得了动员的自体CD34 +细胞，并用能编码成人血红蛋白（HbA）的LentiGlobin BB305载体进行了离体转导。 T87Q氨基酸取代（HbAT87Q）。患者接受清髓性白消安调理后，再注入细胞。随后，我们监测了不良事件，载体整合以及具有复制能力的慢病毒的水平。功效评估包括总血红蛋白和HbAT87Q的水平，输血需求和平均载体拷贝数。

结果

在输注基因修饰细胞后的中位时间为26个月（15到42个范围），具有非β0/β0基因型的13例患者中只有1例停止了接受红细胞输注。HbAT87Q的水平范围为每分升3.4至10.0 g，总血红蛋白的水平范围为每分升8.2至13.7 g。在血红蛋白水平接近正常范围的被评估患者中，可实现对促红细胞生成的生物学指标的校正。在9位具有β0/β0基因型或两个拷贝的IVS1-110突变的患者中，年平均输血量减少了73％，并且3例患者中止了红细胞输血。与治疗相关的不良事件是自体干细胞移植相关的典型事件。没有观察到与载体整合有关的克隆优势。

结论

用BB305载体转导的自体CD34 +细胞进行基因治疗可以减少或消除22名严重β地中海贫血患者的长期红细胞输注的需要，而不会产生与药物相关的严重不良事件。（由Bluebird Bio和其他公司资助； HGB-204和HGB-205 ClinicalTrials.gov编号，NCT01745120和NCT02151526。）

免费快速视频摘要
LentiGlobin基因疗法可治疗β-地中海贫血
 02:03