Hamed Eman M, Meabed Mohamed Hussein, Aly Usama Farghaly, Hussein Raghda R S
Department of Pharmaceutics and Clinical Pharmacy; Faculty of Pharmacy; Nahda University, Nahda, Egypt.
Professor of Haematology; Faculty of Medicine; Beni-Suef University, Beni Suef, Egypt.
Curr Drug Targets. 2019;20(16):1603-1623. doi: 10.2174/1389450120666190726155733.
Beta-thalassemia is a genetic disorder characterized by the impaired synthesis of the betaglobin chain of adult hemoglobin. The disorder has a complex pathophysiology that affects multiple organ systems. The main complications of beta thalassemia are ineffective erythropoiesis, chronic hemolytic anemia and hemosiderosis-induced organ dysfunction. Regular blood transfusions are the main therapy for beta thalassemia major; however, this treatment can cause cardiac and hepatic hemosiderosis - the most common cause of death in these patients. This review focuses on unique future therapeutic interventions for thalassemia that reverse splenomegaly, reduce transfusion frequency, decrease iron toxicity in organs, and correct chronic anemia. The targeted effective protocols include hemoglobin fetal inducers, ineffective erythropoiesis correctors, antioxidants, vitamins, and natural products. Resveratrol is a new herbal therapeutic approach which serves as fetal Hb inducer in beta thalassemia. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for beta thalassemia major and is preferred over iron chelation and blood transfusion for ensuring long life in these patients. Meanwhile, several molecular therapies, such as ActRIIB/IgG1 Fc recombinant protein, have emerged to address complications of beta thalassemia or the adverse effects of current drugs. Regarding gene correction strategies, a phase III trial called HGB-207 (Northstar-2; NCT02906202) is evaluating the efficacy and safety of autologous cell transplantation with LentiGlobin. Advanced gene-editing approaches aim to cut DNA at a targeted site and convert HbF to HbA during infancy, such as the suppression of BCL11A (B cell lymphoma 11A), HPFH (hereditary persistence of fetal hemoglobin) and zinc-finger nucleases. Gene therapy is progressing rapidly, with multiple clinical trials being conducted in many countries and the promise of commercial products to be available in the near future.
β地中海贫血是一种遗传性疾病，其特征是成人血红蛋白的β珠蛋白链合成受损。该疾病具有复杂的病理生理学，会影响多个器官系统。β地中海贫血的主要并发症是无效红细胞生成、慢性溶血性贫血和铁过载导致的器官功能障碍。定期输血是重型β地中海贫血的主要治疗方法；然而，这种治疗会导致心脏和肝脏铁过载，这是这些患者最常见的死亡原因。本综述重点关注地中海贫血未来独特的治疗干预措施，这些措施可逆转脾肿大、减少输血频率、降低器官中铁毒性并纠正慢性贫血。有针对性的有效方案包括胎儿血红蛋白诱导剂、无效红细胞生成纠正剂、抗氧化剂、维生素和天然产物。白藜芦醇是一种新的草药治疗方法，可作为β地中海贫血的胎儿血红蛋白诱导剂。造血干细胞移植（HSCT）是重型β地中海贫血的唯一治愈性疗法，与铁螯合和输血相比，更有利于确保这些患者的长期生存。同时，一些分子疗法，如激活素受体IIB/IgG1 Fc重组蛋白，已出现以解决β地中海贫血的并发症或当前药物的不良反应。关于基因校正策略，一项名为HGB-207（北极星-2；NCT02906202）的III期试验正在评估慢病毒载体介导的自体细胞移植的疗效和安全性。先进的基因编辑方法旨在在婴儿期在靶向位点切割DNA并将HbF转化为HbA，例如抑制BCL11A（B细胞淋巴瘤11A）、遗传性胎儿血红蛋白持续存在（HPFH）和锌指核酸酶。基因治疗进展迅速，许多国家正在进行多项临床试验，有望在不久的将来推出商业产品。
