小柯机器人

美国纪念斯隆凯特琳癌症中心Michel Sadelain研究团队开展的1期试验表明，慢病毒珠蛋白基因治疗可减缓成人β-地中海贫血症。相关论文于2022年1月3日发表在《自然-医学》杂志上。

研究人员对4名输血依赖性β-地中海贫血成年患者进行了6-8年随访，这些患者在降低强度调节(RIC)后参与了输注用TNS9.3.55慢病毒珠蛋白载体转导自体 CD34⁺细胞的1期临床试验（NCT01639690）。研究主要监测了患者的插入突变和有复制能力慢病毒的产生（RIC后输注产品的安全性和耐受性为主要终点），而转基因自体CD34⁺细胞的植入、β-珠蛋白基因的表达和移植后输血要求为次要终点。在调节和细胞产品输注过程中没有出现意外的安全问题。造血基因标记非常稳定但很低，尽管没有实现输血独立性但减少了两名患者的输血需求。

该研究结果表明，非清髓性调理可以实现持久的干细胞移植，但需要转导最低剂量治疗性CD34⁺细胞。中度克隆扩增与癌症相关基因附近的整合相关，表明干/祖细胞中珠蛋白载体的非红细胞活性。这些相关发现说明应该对携带珠蛋白载体患者进行必要监测。

据介绍，β-地中海贫血是由血红蛋白β链缺乏或表达不足引起的遗传性贫血症。

附：英文原文

Title: Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial

Author: Boulad, Farid, Maggio, Aurelio, Wang, Xiuyan, Moi, Paolo, Acuto, Santina, Kogel, Friederike, Takpradit, Chayamon, Prockop, Susan, Mansilla-Soto, Jorge, Cabriolu, Annalisa, Odak, Ashlesha, Qu, Jinrong, Thummar, Keyur, Du, Fang, Shen, Lingbo, Raso, Simona, Barone, Rita, Di Maggio, Rosario, Pitrolo, Lorella, Giambona, Antonino, Mingoia, Maura, Everett, John K., Hokama, Pascha, Roche, Aoife M., Cantu, Vito Adrian, Adhikari, Hriju, Reddy, Shantan, Bouhassira, Eric, Mohandas, Narla, Bushman, Frederic D., Rivire, Isabelle, Sadelain, Michel

Issue&Volume: 2022-01-03

Abstract: 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.

DOI: 10.1038/s41591-021-01554-9

Source: https://www.nature.com/articles/s41591-021-01554-9

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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