Weill Cornell Medical College, Department of Pediatrics, Division of Hematology-Oncology, New York, NY 10021, USA.
Transl Res. 2013 Apr;161(4):293-306. doi: 10.1016/j.trsl.2012.12.011. Epub 2013 Jan 19.
Hemoglobinopathies are genetic inherited conditions that originate from the lack or malfunction of the hemoglobin (Hb) protein. Sickle cell disease (SCD) and thalassemia are the most common forms of these conditions. The severe anemia combined with complications that arise in the most affected patients raises the necessity for a cure to restore hemoglobin function. The current routine therapies for these conditions, namely transfusion and iron chelation, have significantly improved the quality of life in patients over the years, but still fail to address the underlying cause of the diseases. A curative option, allogeneic bone marrow transplantation is available, but limited by the availability of suitable donors and graft-vs-host disease. Gene therapy offers an alternative approach to cure patients with hemoglobinopathies and aims at the direct recovery of the hemoglobin function via globin gene transfer. In the last 2 decades, gene transfer tools based on lentiviral vector development have been significantly improved and proven curative in several animal models for SCD and thalassemia. As a result, clinical trials are in progress and 1 patient has been successfully treated with this approach. However, there are still frontiers to explore that might improve this approach: the stoichiometry between the transgenic hemoglobin and endogenous hemoglobin with respect to the different globin genetic mutations; donor cell sourcing, such as the use of induced pluripotent stem cells (iPSCs); and the use of safer gene insertion methods to prevent oncogenesis. With this review we will provide insights about (1) the different lentiviral gene therapy approaches in mouse models and human cells; (2) current and planned clinical trials; (3) hurdles to overcome for clinical trials, such as myeloablation toxicity, insertional oncogenesis, and high vector expression; and (4) future perspectives for gene therapy, including safe harbors and iPSCs technology.
血红蛋白病是由血红蛋白（Hb）蛋白缺乏或功能障碍引起的遗传性疾病。镰状细胞病（SCD）和地中海贫血是最常见的形式。严重的贫血加上最受影响的患者出现的并发症，需要一种治疗方法来恢复血红蛋白功能。这些疾病的常规治疗方法，即输血和铁螯合，近年来显著提高了患者的生活质量，但仍未能解决疾病的根本原因。一种可行的治疗方法，异体骨髓移植是可用的，但受到合适供体的可用性和移植物抗宿主病的限制。基因治疗为治疗血红蛋白病患者提供了一种替代方法，旨在通过珠蛋白基因转移直接恢复血红蛋白功能。在过去的 20 年中，基于慢病毒载体开发的基因转移工具得到了显著改进，并在 SCD 和地中海贫血的几种动物模型中证明了其疗效。因此，临床试验正在进行中，已有 1 名患者成功接受了这种治疗方法。然而，仍有一些前沿领域需要探索，以改进这种方法：转基因血红蛋白与不同珠蛋白基因突变的内源性血红蛋白之间的化学计量比；供体细胞来源，如诱导多能干细胞（iPSCs）的使用；以及使用更安全的基因插入方法来预防致癌作用。通过这篇综述，我们将提供关于以下方面的见解：（1）不同的慢病毒基因治疗方法在小鼠模型和人类细胞中的应用；（2）当前和计划中的临床试验；（3）临床试验中需要克服的障碍，如骨髓清除毒性、插入性致癌作用和高载体表达；（4）基因治疗的未来展望，包括安全港和 iPSCs 技术。
