Cystic Fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and CF patients require life-long treatment. Although CFTR modulators show a great potential for treating most CF patients, some individuals may not tolerate the treatment. In addition, there is no effective therapy for patients with some rare CFTR mutations, such as class I CF mutations, which lead to a lack of CFTR protein production. Therefore, other therapeutic strategies, such as gene therapy, have to be investigated. Currently, immune responses to gene therapy vectors and transgene products are a major obstacle to applying CF gene therapy to clinical applications. In this study, we examined the effects of cyclophosphamide on the modulation of host immune responses and for the improvement of the CFTR transgene expression in the repeated delivery of helper-dependent adenoviral (HD-Ad) vectors to mouse lungs. We have found that cyclophosphamide significantly decreased the expression of T cell genes, such as CD3 (cluster of differentiation 3) and CD4, and reduced their infiltration into mouse lung tissues. We have also found that the levels of the anti-adenoviral antibody and neutralizing activity as well as B-cell infiltration into the mouse lung tissues were significantly reduced with this treatment. Correspondingly, the expression of the human CFTR transgene has been significantly improved with cyclophosphamide administration compared to the group with no treatment. These data suggest that the sustained expression of the human CFTR transgene in mouse lungs through repeated vector delivery can be achieved by transient immunosuppression.

中文翻译：

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克服小鼠气道中辅助依赖型腺病毒载体介导的长期 CFTR 表达的免疫学挑战

囊性纤维化 (CF) 是由囊性纤维化跨膜传导调节 (CFTR) 基因突变引起的，CF 患者需要终生治疗。尽管 CFTR 调节剂显示出治疗大多数 CF 患者的巨大潜力，但有些人可能无法耐受这种治疗。此外，对于一些罕见的 CFTR 突变，如 I 类 CF 突变，导致 CFTR 蛋白产生不足的患者，也没有有效的治疗方法。因此，必须研究其他治疗策略，例如基因治疗。目前，对基因治疗载体和转基因产品的免疫反应是将 CF 基因治疗应用于临床的主要障碍。在这项研究中，我们检查了环磷酰胺对宿主免疫反应的调节以及在辅助依赖性腺病毒 (HD-Ad) 载体向小鼠肺重复递送过程中改善 CFTR 转基因表达的影响。我们发现环磷酰胺显着降低了 T 细胞基因的表达，如 CD3（分化簇 3）和 CD4，并减少了它们对小鼠肺组织的浸润。我们还发现，这种治疗显着降低了抗腺病毒抗体和中和活性以及 B 细胞浸润到小鼠肺组织中的水平。相应地，与未治疗组相比，环磷酰胺给药组人 CFTR 转基因的表达得到显着改善。