Herzog Roland W, Cao Ou, Hagstrom J Nathan, Wang Lixin
Department of Pediatrics, University of Florida, Cellular and Molecular Therapy, Alachua, FL 32615, USA.
Expert Opin Biol Ther. 2006 May;6(5):509-22. doi: 10.1517/14712598.6.5.509.
Gene therapy, a molecular medicine based on vector-mediated transfer of therapeutic genes, holds promise for a cure of monogenetic inherited diseases. In recent years, tremendous progress has been reported in the treatment of haematological disorders: clinical trials in severe combined immune deficiencies have been successful by using retroviral vectors to express target genes in haematopoietic stem cells, which after transplantation efficiently reconstituted the immune system concomitant with substantial improvement in the clinical status of patients. Conversely, unexpected adverse events were also encountered. In other work, progress towards clinical studies on ex vivo gene transfer for Fanconi anaemia and haemoglobinopathies has been made. Each approach features a unique treatment strategy and also faces various impediments to success. In the case of the X-linked bleeding disorder haemophilia, several Phase I/II clinical trials were conducted, including in vivo administration of viral vectors to skeletal muscle and liver. Adeno-associated viral gene transfer of coagulation Factor IX has been documented in human subjects, reaching therapeutic levels after infusion into a hepatic blood vessel. However, sustained expression of therapeutic levels (as shown in large animal models of haemophilia) has not yet been achieved in humans. In general, long-term follow-up will be important for assessment of the safety of all existing gene therapy strategies.
基因治疗是一种基于载体介导的治疗性基因转移的分子医学，有望治愈单基因遗传病。近年来，血液系统疾病的治疗取得了巨大进展：在重症联合免疫缺陷的临床试验中，通过使用逆转录病毒载体在造血干细胞中表达靶基因获得成功，移植后这些细胞有效地重建了免疫系统，同时患者的临床状况有了显著改善。然而，也遇到了意外的不良事件。在其他研究中，针对范可尼贫血和血红蛋白病的体外基因转移临床研究也取得了进展。每种方法都有独特的治疗策略，也面临着各种成功障碍。对于X连锁出血性疾病血友病，已经进行了多项I/II期临床试验，包括向骨骼肌和肝脏体内给药病毒载体。凝血因子IX的腺相关病毒基因转移已在人体受试者中得到证实，注入肝血管后达到治疗水平。然而，在人类中尚未实现治疗水平的持续表达（如在血友病的大型动物模型中所示）。一般来说，长期随访对于评估所有现有基因治疗策略的安全性至关重要。
