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

Shiqi Li; Sikai Ling; Dawei Wang; Xiaoyuan Wang; Fangyuan Hao; Liufan Yin; Zhongtao Yuan; Lin Liu; Lin Zhang; Yu Li; Yingnian Chen; Le Luo; Ying Dai; Lihua Zhang; Lvzhe Chen; Dongjie Deng; Wei Tang; Sujiang Zhang; Sanbin Wang; Yujia Cai

doi:10.1016/j.stem.2024.04.021

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

Cell Stem Cell. 2024 May 10:S1934-5909(24)00175-9. doi: 10.1016/j.stem.2024.04.021. Online ahead of print.

Authors

Shiqi Li¹, Sikai Ling², Dawei Wang³, Xiaoyuan Wang⁴, Fangyuan Hao⁴, Liufan Yin⁵, Zhongtao Yuan¹, Lin Liu¹, Lin Zhang⁴, Yu Li¹, Yingnian Chen¹, Le Luo¹, Ying Dai¹, Lihua Zhang¹, Lvzhe Chen¹, Dongjie Deng⁵, Wei Tang³, Sujiang Zhang³, Sanbin Wang⁶, Yujia Cai⁷

Affiliations

¹ 920th Hospital of Joint Logistics Support Force of People's Liberation Army of China, Kunming, Yunnan 650100, China.
² Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China; BDgene Therapeutics, Shanghai 200240, China.
³ Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁴ BDgene Therapeutics, Shanghai 200240, China.
⁵ Sequanta Technologies, Shanghai 200131, China.
⁶ 920th Hospital of Joint Logistics Support Force of People's Liberation Army of China, Kunming, Yunnan 650100, China. Electronic address: sanbin1011@163.com.
⁷ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: yujia.cai@sjtu.edu.cn.

PMID: 38759653
DOI: 10.1016/j.stem.2024.04.021

Abstract

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.

Keywords: CD34(+) cell; HSPC; gene addition; gene therapy; globin; insulator; lentivirus; red blood cell; single-cell DNA sequencing; β(0)/β(0) thalassemia.