Bigger B W, Siapati E K, Mistry A, Waddington S N, Nivsarkar M S, Jacobs L, Perrett R, Holder M V, Ridler C, Kemball-Cook G, Ali R R, Forbes S J, Coutelle C, Wright N, Alison M, Thrasher A J, Bonnet D, Themis M
Gene Therapy Research Group, Faculty of Medicine, Imperial College London, South Kensington, UK.
Gene Ther. 2006 Jan;13(2):117-26. doi: 10.1038/sj.gt.3302638.
Immune responses against an introduced transgenic protein are a potential risk in many gene replacement strategies to treat genetic disease. We have developed a gene delivery approach for hemophilia B based on lentiviral expression of human factor IX in purified hematopoietic stem cells. In both normal C57Bl/6J and hemophilic 129/Sv recipient mice, we observed the production of therapeutic levels of human factor IX, persisting for at least a year with tolerance to human factor IX antigen. Secondary and tertiary recipients also demonstrate long-term production of therapeutic levels of human factor IX and tolerance, even at very low levels of donor chimerism. Furthermore, in hemophilic mice, partial functional correction of treated mice and phenotypic rescue is achieved. These data show the potential of a stem cell approach to gene delivery to tolerize recipients to a secreted foreign transgenic protein and, with appropriate modification, may be of use in developing treatments for other genetic disorders.
在许多用于治疗遗传疾病的基因替代策略中，针对引入的转基因蛋白的免疫反应是一种潜在风险。我们基于在纯化的造血干细胞中慢病毒表达人凝血因子IX，开发了一种针对B型血友病的基因递送方法。在正常的C57Bl/6J小鼠和血友病129/Sv受体小鼠中，我们都观察到了治疗水平的人凝血因子IX的产生，其持续至少一年且对人凝血因子IX抗原具有耐受性。二级和三级受体也表现出治疗水平的人凝血因子IX的长期产生和耐受性，即使在供体嵌合率非常低的情况下也是如此。此外，在血友病小鼠中，实现了对治疗小鼠的部分功能纠正和表型挽救。这些数据表明干细胞基因递送方法有潜力使受体对分泌的外源转基因蛋白产生耐受性，并且经过适当修改后，可能可用于开发其他遗传疾病的治疗方法。
