IMMUNOSUPPRESSION IN PROLONGING TRANSGENE EXPRESSION: CYSTIC FIBROSIS

囊性纤维化(CF)中的基因突变影响 一种细胞离子转运调节因子的表达。初级阶段 这种缺陷的表现出现在肺、肝和胰腺。 用腺病毒(ADV)进行Cf基因置换的I期临床试验 已知能有效地将基因输送到肺部的载体 肝脏，由于宿主对ADV的反应，成功有限 缩短CFTR转基因表达的持续时间。CD+4+ 淋巴细胞对这些反应和消耗抗-cd4至关重要。 抗体延长了Adv在啮齿动物肺部的表达。我们计划 在恒河猴身上测试各种免疫抑制方案，以评估 它们对重组腺病毒载体转基因表达的影响 肺部。在这个试验项目中，给一只恒河猴接种了疫苗 支气管腔内注射含有LacZ报告基因的AdV载体。 3天后接种部位取材，转基因 结果表明，该基因具有良好的表达能力。这些初步结果被用于一项 赠款申请，已由Cytic提供部分资金 纤维化基金会。目前正在计划进行更多的研究。

The genetic mutation in cystic fibrosis (CF) affects the expression of a regulator of cellular ion transport. The primary manifestations of this defect occur in the lung, liver, and pancreas. Phase-I clinical trials of CF-gene replacement, using adenoviral (AdV) vectors which are known to efficiently deliver genes to the lung and liver, have had limited success because host responses to the AdV reduce the duration of transgenic expression of CFTR. CD4+ lymphocytes are critical to these responses and depleting anti-CD4 antibody prolongs AdV expression in the lungs of rodents. We plan to test various immunosuppressive protocols in rhesus monkeys to evaluate their effect on transgene expression of AdV vectors inoculated into the lung. For this pilot project, a rhesus monkey was inoculated intrabronchially with an AdV vector containing the LacZ reporter gene. The inoculation site was biopsied 3 days later, and transgene expression was demonstrated. These preliminary results were used in a grant application, which has been partially funded by the Cystic Fibrosis Foundation. Additional studies are currently being planned.