地中海贫血基因治疗新型载体的开发和机理研究

β-地中海贫血是由于编码β-珠蛋白（HBB）的基因发生突变所导致的溶血性贫血疾病。当前临床上的常规治疗手段包括规范化输血、异体造血干细胞移植等，但都存在一定的局限性，慢病毒基因治疗有望成为根治β-地中海贫血的重要替代方法。利用慢病毒载体实现HBB整合补偿已经有多项临床试验取得显著成效，基于BB305载体的药物Zynteglo（Lenti-Globin）已获欧盟批准上市，但高昂的治疗费用限制了其在临床治疗上的进一步推广。基于前期的研究积累，我们认为通过对载体启动子、增强子和内含子的重新设计和系统测试，将有望开发出具有中国自主知识产权的HBB慢病毒载体。以目前最成功的BB305载体为阳性对照，我们预期优化后的载体包装滴度将至少提高2倍，同时HBB表达水平将提高50%以上，治疗费用大幅度降低，这样能够以国人负担得起的治疗费用，实现地贫基因治疗的临床转化，改善中国10万重症地贫患者的生存质量。

β-thalassemia is a hemolytic anemia disease caused by a β-globin (HBB) gene mutation. Current clinical treatments include standardized blood transfusions and allogeneic hematopoietic stem cell transplantation, but they all have certain limitations. Gene therapy based lentiviral vector has become an essential alternative strategy to cure β-thalassemia. Using lentiviral vectors to achieve HBB integration has achieved remarkable clinical results in multiple trials. The drug Zynteglo (Lenti-Globin), based on the BB305 HBB-expressing lentiviral vector, has been approved by the European Union. Still, the high treatment cost limits its further promotion in clinical treatment. Building upon our previous experience in this field, we propose to develop a novel HBB lentiviral vector by optimizing the promoters, enhancers, and introns. Compared to the currently most successful BB305 vector, we expect that the titers of the optimized vector will increase by ~2-fold, and the HBB expression levels increase by ~50%. As a result, the therapeutic costs will be reduced considerably, and thus, the new therapy will be more affordable. The novel HBB lentiviral vector will expedite the clinical translation of β-thalassemia gene therapy and improve the life quality of 100,000 patients in China.