Dept. Pediatrics, University of Florida, Gainesville, FL, USA.
Cell Immunol. 2019 Aug;342:103658. doi: 10.1016/j.cellimm.2017.05.006. Epub 2017 May 29.
After two decades of research, in vivo gene transfer with adeno-associated viral (AAV) vectors has now resulted in successful treatments and even cures for several human diseases. However, the potential for immune responses against the therapeutic gene products remains one of the concerns as this approach is broadened to more patients, diverse diseases, and target organs. Immune responses following gene transfer of coagulation factor IX (FIX) for the treatment of the bleeding disorder hemophilia B has been extensively investigated in multiple animal models. Findings from these studies have not only influenced clinical trial design but have broader implications for other diseases. The impact of vector design and dose, as well as target organ/route of administration on humoral and cellular immune responses are reviewed. Furthermore, the potential for tolerance induction by hepatic gene transfer or combination with immune modulation is discussed.
经过二十年的研究，腺相关病毒（AAV）载体的体内基因转移现在已经成功地治疗了几种人类疾病，甚至治愈了这些疾病。然而，随着这种方法被更广泛地应用于更多的患者、更多样化的疾病和目标器官，针对治疗基因产物产生免疫反应的可能性仍然是人们关注的问题之一。在多种动物模型中，针对凝血因子 IX（FIX）的基因转移治疗出血性疾病乙型血友病的研究已经广泛地研究了免疫反应。这些研究的结果不仅影响了临床试验的设计，而且对其他疾病也有更广泛的影响。本文综述了载体设计和剂量以及目标器官/给药途径对体液和细胞免疫反应的影响。此外，还讨论了通过肝基因转移或与免疫调节联合诱导耐受的可能性。
