Adenovirus-Mediated Gene Transfer into Selected Liver Segments Using a Vascular Exclusion Technique
Adenovirus-Mediated Gene Transfer into Selected Liver Segments Using a Vascular Exclusion Technique
复制标题
使用血管排除技术将腺病毒介导的基因转移到选定的肝段中
作者：
B. Scholl;P. Gervaz;O. Martinet;R. Ksontini;T. Krueger;R. Sahli;M. Gillet
腺病毒介导的基因治疗受到严重的病毒相关毒性的阻碍，特别是对肝脏的毒性。本研究的目的是测试血管排斥技术在选定肝段内实现转基因表达的能力，从而最大限度地减少病毒和转基因产品对肝脏的毒性。将表达绿色荧光蛋白（GFP）报告基因的e1 - e3缺失复制缺陷腺病毒注射到BDIX大鼠的门静脉中，同时夹闭门静脉分支至肝II、III、IV、V和VIII节段。测定不同肝脏组织中GFP的表达和炎症浸润，并与未夹持门静脉病毒载体的动物肝脏进行比较。GFP在选择性灌注肝段中的表达明显高于未灌注肝段（p < 0.0001），也高于未夹持门静脉的肝段（p < 0.0001）。因此，与其他各组相比，选择性灌注肝段炎症浸润更强烈（p < 0.0001）。肺、肾无荧光，脾无荧光。腺病毒介导的基因转移到肝脏的临床用途在很大程度上取决于其肝毒性的降低。在注射过程中夹紧选定的门静脉分支，可以将感兴趣的基因递送到目标肝段。局限于特定肝段的转基因表达可能对局灶性肝病（包括转移性肝病）的治疗有用。
Adenovirus-mediated gene therapy is hampered by severe virus-related toxicity, especially to the liver. The aim of the present study was to test the ability of a vascular exclusion technique to achieve transgene expression within selected liver segments, thus minimizing both viral and transgene product toxicity to the liver. An E1-E3-deleted replication-deficient adenovirus expressing a green fluorescent protein (GFP) reporter gene was injected into the portal vein of BDIX rats, with simultaneous clamping of the portal vein tributaries to liver segments II, III, IV, V, and VIII. GFP expression and inflammatory infiltrate were measured in the different segments of the liver and compared with those of the livers of animals receiving the viral vector in the portal vein without clamping. The GFP expression was significantly higher in the selectively perfused segments of the liver as compared with the non-perfused segments (p < 0.0001) and with the livers of animals that received the vector in the portal vein without clamping (p < 0.0001). Accordingly, the inflammatory infiltrate was more intense in the selectively perfused liver segments as compared with all other groups (p < 0.0001). Fluorescence was absent in lungs and kidneys and minimal in spleen. The clinical usefulness of adenovirus-mediated gene transfer to the liver largely depends on the reduction of its liver toxicity. Clamping of selected portal vein branches during injection allows for delivery of genes of interest to targeted liver segments. Transgene expression confined to selected liver segments may be useful in the treatment of focal liver diseases, including metastases.
影响因子：
13.8
作者：
CUBITT, AB;HEIM, R;TSIEN, RY
通讯作者：
TSIEN, RY
影响因子：
4.2
作者：
Pastore, L;Morral, N;Beaudet, AL
通讯作者：
Beaudet, AL
DOI：
10.1073/pnas.96.22.12816
发表时间：
1999-10-26
影响因子：
11.1
作者：
Morral, N;O'Neal, W;Beaudet, AL
通讯作者：
Beaudet, AL