Modified lentiviral globin gene therapy for pediatric β0/β0 transfusion-dependent β-thalassemia: A single-center, single-arm pilot trial

• Published in: Cell stem cell Vol. 31; no. 7; pp. 961 - 973.e8
• Main Authors: Li, Shiqi, Ling, Sikai, Wang, Dawei, Wang, Xiaoyuan, Hao, Fangyuan, Yin, Liufan, Yuan, Zhongtao, Liu, Lin, Zhang, Lin, Li, Yu, Chen, Yingnian, Luo, Le, Dai, Ying, Zhang, Lihua, Chen, Lvzhe, Deng, Dongjie, Tang, Wei, Zhang, Sujiang, Wang, Sanbin, Cai, Yujia
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.07.2024
• Subjects: CD34+ cell; gene addition; gene therapy; globin; HSPC; insulator; lentivirus; red blood cell; single-cell DNA sequencing; β0/β0 thalassemia; single-cell DNA sequencing; β0/β0 thalassemia; globin; gene therapy; gene addition; CD34+ cell; insulator; lentivirus; HSPC; red blood cell
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2024.04.021

β0/β0 thalassemia is the most severe type of transfusion-dependent β-thalassemia (TDT) and is still a challenge facing lentiviral gene therapy. Here, we report the interim analysis of a single-center, single-arm pilot trial (NCT05015920) evaluating the safety and efficacy of a β-globin expression-optimized and insulator-engineered lentivirus-modified cell product (BD211) in β0/β0 TDT. Two female children were enrolled, infused with BD211, and followed up for an average of 25.5 months. Engraftment of genetically modified hematopoietic stem and progenitor cells was successful and sustained in both patients. No unexpected safety issues occurred during conditioning or after infusion. Both patients achieved transfusion independence for over 22 months. The treatment extended the lifespan of red blood cells by over 42 days. Single-cell DNA/RNA-sequencing analysis of the dynamic changes of gene-modified cells, transgene expression, and oncogene activation showed no notable adverse effects. Optimized lentiviral gene therapy may safely and effectively treat all β-thalassemia. [Display omitted] •An insulator-engineered lentivirus rebalanced β- and α-chains in β0/β0 thalassemia•Single-cell DNA/RNA-sequencing analysis showed no notable adverse effects•BD211 reduced ineffective erythropoiesis and extended lifespan of red blood cells Li et al. reported an interim analysis of a single-center, single-arm pilot trial evaluating a β-globin expression-optimized and insulator-engineered lentivirus-modified cell product in the most severe β-thalassemia (β0/β0). The therapy rebalanced β-globin and α-globin chains in patients who achieved transfusion independence for nearly 2 years without any notable adverse effects.