β-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the β chain of hemoglobin. Here we report 6–8-year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34⁺ cells transduced with the TNS9.3.55 lentiviral globin vector after reduced-intensity conditioning (RIC) in a phase 1 clinical trial (NCT01639690). Patients were monitored for insertional mutagenesis and the generation of a replication-competent lentivirus (safety and tolerability of the infusion product after RIC—primary endpoint) and engraftment of genetically modified autologous CD34⁺ cells, expression of the transduced β-globin gene and post-transplant transfusion requirements (efficacy—secondary endpoint). No unexpected safety issues occurred during conditioning and cell product infusion. Hematopoietic gene marking was very stable but low, reducing transfusion requirements in two patients, albeit not achieving transfusion independence. Our findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment but underscore a minimum CD34⁺ cell transduction requirement for effective therapy. Moderate clonal expansions were associated with integrations near cancer-related genes, suggestive of non-erythroid activity of globin vectors in stem/progenitor cells. These correlative findings highlight the necessity of cautiously monitoring patients harboring globin vectors.

β-地中海贫血是遗传性贫血，由血红蛋白 β 链缺失或生成不足引起。在此，我们报告了四名输血依赖性 β 地中海贫血成年患者的 6-8 年随访，这些患者在一个阶段的降低强度调节 (RIC) 后输注了用 TNS9.3.55 慢病毒球蛋白载体转导的自体 CD34 ⁺细胞1 项临床试验（NCT01639690）。监测患者的插入诱变和具有复制能力的慢病毒的产生（RIC后输注产品的安全性和耐受性——主要终点）以及转基因自体CD34+细胞的植入、转导的β-珠蛋白基因的表达^和后移植输血要求（功效——次要终点）。在调理和细胞产品输注过程中没有发生意外的安全问题。造血基因标记非常稳定但较低，减少了两名患者的输血需求，尽管没有实现输血独立。我们的研究结果表明，非清髓性调理可以实现持久的干细胞植入，但强调有效治疗的最低 CD34 ^{+细胞转导要求。}中度克隆扩增与癌症相关基因附近的整合相关，表明干细胞/祖细胞中珠蛋白载体具有非红细胞活性。这些相关发现强调了谨慎监测携带珠蛋白载体的患者的必要性。