Herzog Roland W, Arruda Volder R
The Children's Hospital of Philadelphia, Abramson Research Center, PA 19104, USA.
Expert Rev Cardiovasc Ther. 2003 Jul;1(2):215-32. doi: 10.1586/14779072.1.2.215.
The past 3 years have been characterized by a number of impressive advances as well as setbacks in gene therapy for genetic disease. Children with X-linked severe combined immunodeficiency disorder (SCID-X1) have shown almost complete reconstitution of their immune system after receiving retrovirally transduced autologous CD34+ hematopoietic stem cells (HSCs). However, two of 11 treated patients subsequently developed a leukemia-like disease probablydue to the undesired activation of an oncogene. Gene transfer to HSCs resulted in substantial correction of immune function and multi-lineage engraftment in two patients with adenosine deaminase (ADA)-SCID. Several Phase I clinical trials for treatment of hemophilia A and B have been initiated or completed. Partial correction of hemophilia A, albeit transient, has been reported by ex vivo gene transfer to autologous fibroblasts. Intramuscular injection of adeno-associated viral (AAV) vector to patients with severe hemophilia B resulted in evidence of Factor IX gene transfer to skeletal muscle and a separate trial based on hepatic infusion of AAV vector is ongoing. Sustained therapeutic levels of coagulation factor expression have been achieved in preclinical models using retroviral, lentiviral, AAV and high capacity adenoviral vectors. Efficient lentiviral gene transfer to HSC in murine models of beta-thalassemia and sickle cell disease demonstrated sustained phenotypic correction.
在过去三年里，针对遗传疾病的基因治疗取得了一些令人瞩目的进展，但也遭遇了挫折。患有X连锁重症联合免疫缺陷症（SCID-X1）的儿童在接受逆转录病毒转导的自体CD34+造血干细胞（HSC）后，其免疫系统几乎完全重建。然而，11名接受治疗的患者中有两名随后患上了类似白血病的疾病，可能是由于一种致癌基因的意外激活。将基因转移到造血干细胞中，使得两名腺苷脱氨酶（ADA）-SCID患者的免疫功能得到了实质性纠正，并且实现了多谱系植入。已经启动或完成了几项治疗A型和B型血友病的I期临床试验。通过将基因体外转移到自体成纤维细胞中，已报道对A型血友病有部分纠正，尽管是短暂的。对重度B型血友病患者进行肌肉注射腺相关病毒（AAV）载体，结果显示有证据表明因子IX基因已转移至骨骼肌，并且一项基于向肝脏输注AAV载体的单独试验正在进行中。在临床前模型中，使用逆转录病毒、慢病毒、AAV和高容量腺病毒载体已实现了凝血因子表达的持续治疗水平。在β地中海贫血和镰状细胞病的小鼠模型中，将慢病毒基因有效转移至造血干细胞显示出持续的表型纠正。
