ADENOVIRUS-MEDIATED TRANSFER OF THE CFTR GENE TO LUNG OF NONHUMAN-PRIMATES - TOXICITY STUDY
ADENOVIRUS-MEDIATED TRANSFER OF THE CFTR GENE TO LUNG OF NONHUMAN-PRIMATES - TOXICITY STUDY
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DOI：
10.1089/hum.1993.4.6-771
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发表时间：
1993-12-01
影响因子：
4.2
通讯作者：
WILSON, JM
中科院分区：
文献类型：
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作者：
SIMON, RH;ENGELHARDT, JF;WILSON, JM
为了准备囊性纤维化（CF）基因治疗的人体试验，我们进行了一项将基因转移到狒狒肺部的临床前研究。将含有人囊性纤维化跨膜传导调节因子（CFTR）和大肠杆菌β -半乳糖糖酶（lacZ）表达盒的重组腺病毒载体通过支气管镜注入14只狒狒的肺有限区域。有关基因表达的范围、分布和持续时间的详细描述，可参见另一篇文章（Engelhardt et al., 1993b）。在这篇文章中，我们报告了毒性研究的结果，其中临床实验室检查、胸部x线片和尸检研究被用来检测不良反应。唯一注意到的不良反应是在接受病毒剂量的动物肺泡腔内的单核细胞炎症反应，这是诱导可检测到的基因表达所必需的。10(7)和10(8)pfu/ml时可见轻微炎症，但10(9)和10(10)pfu/ml时更明显，可见血管周围淋巴细胞和组织细胞浸润。炎症强度在4 ~ 21 d间增加。最严重时，肺泡壁弥漫性损伤伴肺泡内水肿。气道相对完好，尽管肺泡炎症严重。除了胸片显示肺泡浸润外，临床检查不能准确反映肺部炎症的存在，但仅在肺部炎症最强烈的区域。我们得出结论，腺病毒介导的基因转移到狒狒的肺部与高剂量病毒的肺泡炎症的发展有关。
In preparation for human trials of gene therapy for cystic fibrosis (CF), we performed a preclinical study of gene transfer into the lungs of baboons. Recombinant adenovirus vectors containing expression cassettes for human cystic fibrosis transmembrane conductance regulator (CFTR) and Escherichia coli beta-galactosidase (lacZ) were instilled through a bronchoscope into limited regions of lung in 14 baboons. A detailed accounting of the extent, distribution, and duration of gene expression is contained in a companion article (Engelhardt et al., 1993b). In this article, we report the results of toxicity studies in which clinical laboratory tests, chest radiographs, and necropsy studies were used to detect adverse effects. The only adverse effect noted was a mononuclear cell inflammatory response within the alveolar compartment of animals receiving doses of virus that were required to induce detectable gene expression. Minimal inflammation was seen at 10(7) and 10(8) pfu/ml, but at 10(9) and more prominently at 10(10) pfu/ml, a perivascular lymphocytic and histocytic infiltrate was seen. The intensity of inflammation increased between 4 and 21 days. At its greatest intensity, there was diffuse alveolar wall damage with intra-alveolar edema. Airways were relatively spared, despite the intensity of alveolar inflammation. Clinical tests did not accurately reflect the presence of lung inflammation, with the exception of chest radiographs which revealed alveolar infiltrates, but only in regions of lung having the greatest intensity inflammation. We conclude that adenovirus-mediated gene transfer into the lungs of baboons is associated with development of alveolar inflammation at high doses of virus.