A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis.
A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis.
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腺病毒介导的人类囊性纤维化跨膜电导调节基因转移至囊性纤维化个体肺段的 I 期研究。
DOI：
10.1089/10430349950016384
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Wilson,JM
中科院分区：
文献类型：
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作者：
Zuckerman,JB;Robinson,CB;McCoy,KS;Shell,R;Sferra,TJ;Chirmule,N;Magosin,SA;Propert,KJ;Brown-Parr,EC;Hughes,JV;Tazelaar,J;Baker,C;Goldman,MJ;Wilson,JM
通过支气管镜将含重组人囊性纤维化跨膜传导调节因子（CFTR）基因的第三代腺病毒载体以递增剂量递送至传导气道 11名囊性纤维化的志愿者。进行剂量限制性毒性（DLT）、基因转移效率以及对载体施用的细胞介导和体液免疫应答的评估。DLT， 表现为流感样症状和一过性放射学浸润，病毒颗粒总数为2.1 × 1011。利用针对载体序列的寡核苷酸探针进行原位杂交，建立了一种高度特异的基因转移检测方法。载体滴注后4天，在收获的支气管上皮细胞中观察到可检测的基因转移（<1%）， 到第43天降到无法检测的水平腺病毒特异性细胞介导的T细胞在大多数受试者中诱导，尽管仅观察到全身体液免疫应答轻度增加。这些结果证明 在人类中可以用腺病毒载体实现基因转移至下呼吸道上皮，但在天然CF气道中效率低且持续时间短。
A third-generation adenoviral vector containing recombinant human cystic fibrosis transmembrane conductance regulator (CFTR) gene was delivered by bronchoscope in escalating doses to the conducting airway of 11 volunteers with cystic fibrosis. Assessments of dose-limiting toxicity (DLT), efficiency of gene transfer, and cell-mediated and humoral immune responses to vector administration were performed. DLT, manifest by flulike symptoms and transient radiographic infiltrates, was seen at 2.1 X 1011total viral particles. A highly specific assay for gene transfer was developed usingin situhybridization with an oligoprobe against unique vector sequence. Detectable gene transfer was observed in harvested bronchial epithelial cells (<1%) 4 days after vector instillation, which diminished to undetectable levels by day 43. Adenovirus-specific cell-mediated T cells were induced in most subjects, although only mild increases in systemic humoral immune response were observed. These results demonstrate that gene transfer to epithelium of the lower respiratory tract can be achieved in humans with adenoviral vectors but that efficiency is low and of short duration in the native CF airway.