Combination of adeno-associated virus and adenovirus vectors expressing bone morphogenetic protein-2 produces enhanced osteogenic activity in immunocompetent rats
Combination of adeno-associated virus and adenovirus vectors expressing bone morphogenetic protein-2 produces enhanced osteogenic activity in immunocompetent rats
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DOI：
10.1016/j.bbrc.2004.03.098
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发表时间：
2004-05-07
影响因子：
3.1
通讯作者：
Kung, HF
中科院分区：
文献类型：
--
作者：
Chen, Y;Luk, KDK;Kung, HF
我们之前已经表明，使用携带骨形态发生蛋白（BMP）的腺相关病毒（AAV）进行基因治疗是SD大鼠体内新骨形成的一种有前途的策略。然而，它的转导效率相对较低。我们在这里研究是否可以使用 AAV-BMP2 和腺病毒 (Ad)-BMP2 的混合物作为载体系统来实现增强的成骨活性而不引起严重的免疫反应。 SD大鼠的肌肉注射AAV-BMP2、Ad-BMP2或AAV-BMP2/Ad-BMP2混合物，并在注射后八周测定体内骨形成。射线照相检查表明，与单独使用 AAV-BMP2 相比，向 AAV-BMP2 添加低水平的 Ad-BMP2 产生显着更高的新骨形成。组织学和免疫组织学分析显示骨形成区域扩大和 BMP2 长期表达，但没有明显的淋巴细胞浸润。我们的研究结果提供了第一个证据，证明在免疫功能正常的受试者体内引入低水平的腺病毒可以极大地增强 AAV 介导的基因转移，而不诱导严重的免疫反应。这种鸡尾酒载体系统可能提供一种有吸引力的方法来提高基于 AAV 的基因传递效率。 (C) 2004 Elsevier Inc. 保留所有权利。
We have previously shown that gene therapy using adeno-associated virus (AAV) carrying bone morphogenetic proteins (BMPs) is a promising strategy for new bone formation in vivo in SD rats. However, it had a relatively low transduction efficiency. We investigate here whether enhanced osteogenic activity can be achieved without eliciting a severe immune response, using a cocktail of AAV-BMP2 and adenovirus (Ad)-BMP2 as a vector system. The muscles of SD rats were injected with either AAV-BMP2, Ad-BMP2, or an AAV-BMP2/Ad-BMP2 cocktail, and the in vivo bone formation was determined at eight weeks post-injection. Radiographic examination demonstrated that the addition of a low level or Ad-BMP2 to AAV-BMP2 produced significantly higher new bone formation than the use of AAV-BMP2 alone. Histological and immunohistological analysis revealed an enlarged bone-forming area and a long-term BMP2 expression, without pronounced infiltration of lymphocytes. Our results provide the first evidence that the introduction of a low level of adenovirus in vivo in immunocompetent Subjects can greatly enhance AAV-mediated, gene transfer, without inducing severe immune responses. This cocktail vector system may offer an attractive way of improving the efficiency of AAV-based gene delivery. (C) 2004 Elsevier Inc. All rights reserved.