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.
摘要：
β0/β0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。这里,我们报告单中心的中期分析，单臂试点试验（NCT05015920）评估β0/β0TDT中β-珠蛋白表达优化和绝缘子工程的慢病毒修饰细胞产物（BD211）的安全性和有效性。两名女童入学，输注BD211，平均随访25.5个月。在两名患者中，基因修饰的造血干细胞和祖细胞的植入都是成功且持续的。在调节过程中或输注后没有意外的安全问题发生。两名患者均实现了超过22个月的输血独立性。该治疗将红细胞的寿命延长了42天以上。单细胞DNA/RNA测序分析基因修饰细胞的动态变化，转基因表达，癌基因激活无明显不良反应。优化的慢病毒基因疗法可以安全有效地治疗所有β-地中海贫血。
