Dong Alisa C, Rivella Stefano
Division of Hematology-Oncology, Department of Pediatrics, Weill Cornell Medical College, 515 E. 71st St., Room S-709, New York, NY, 10021, USA.
Division of Hematology-Oncology, Department of Pediatrics, Weill Cornell Medical College, 515 E. 71st St., S702, Box 284, New York, NY, 10021, USA.
Adv Exp Med Biol. 2017;1013:155-176. doi: 10.1007/978-1-4939-7299-9_6.
Beta-thalassemia and sickle cell anemia are two of the most common diseases related to the hemoglobin protein. In these diseases, the beta-globin gene is mutated, causing severe anemia and ineffective erythropoiesis. Patients can additionally present with a number of life-threatening co-morbidities, such as stroke or spontaneous fractures. Current treatment involves transfusion and iron chelation; allogeneic bone marrow transplant is the only curative option, but is limited by the availability of matching donors and graft-versus-host disease. As these two diseases are monogenic diseases, they make an attractive setting for gene therapy. Gene therapy aims to correct the mutated beta-globin gene or add back a functional copy of beta- or gamma-globin. Initial gene therapy work was done with oncoretroviral vectors, but has since shifted to lentiviral vectors. Currently, there are a few clinical trials underway to test the curative potential of some of these lentiviral vectors. This review will highlight the work done thus far, and present the challenges still facing gene therapy, such as genome toxicity concerns and achieving sufficient transgene expression to cure those with the most severe forms of thalassemia.
β地中海贫血和镰状细胞贫血是两种与血红蛋白蛋白相关的最常见疾病。在这些疾病中，β珠蛋白基因发生突变，导致严重贫血和无效造血。患者还可能出现一些危及生命的合并症，如中风或自发性骨折。目前的治疗方法包括输血和铁螯合；异基因骨髓移植是唯一的治愈选择，但受到匹配供体的可用性和移植物抗宿主病的限制。由于这两种疾病是单基因疾病，它们成为基因治疗的一个有吸引力的研究对象。基因治疗旨在纠正突变的β珠蛋白基因或重新引入β或γ珠蛋白的功能性拷贝。最初的基因治疗工作是使用逆转录病毒载体进行的，但此后已转向慢病毒载体。目前，有一些临床试验正在进行，以测试其中一些慢病毒载体的治疗潜力。本综述将重点介绍迄今为止所做的工作，并阐述基因治疗仍然面临的挑战，如基因组毒性问题以及实现足够的转基因表达以治愈最严重形式的地中海贫血患者。
