β/β 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 β/β 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.

中文翻译：

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改良慢病毒珠蛋白基因治疗儿童 β0/β0 输血依赖性 β 地中海贫血：单中心、单臂试点试验


β/β地中海贫血是输血依赖性β地中海贫血（TDT）中最严重的类型，仍然是慢病毒基因治疗面临的挑战。在这里，我们报告了一项单中心、单臂试点试验 (NCT05015920) 的中期分析，该试验评估了 β-珠蛋白表达优化和绝缘体工程改造的慢病毒修饰细胞产品 (BD211) 在 β/β 中的安全性和有效性TDT。两名女童入组，注射了 BD211，并进行了平均 25.5 个月的随访。两名患者的转基因造血干细胞和祖细胞的植入均成功并持续。在调理期间或输注后没有发生意外的安全问题。两名患者均已实现输血独立超过 22 个月。该治疗将红细胞的寿命延长了 42 天以上。对基因修饰细胞的动态变化、转基因表达和癌基因激活的单细胞 DNA/RNA 测序分析显示没有显着的副作用。优化的慢病毒基因治疗可以安全有效地治疗所有β地中海贫血。