Kass-Eisler A, Leinwand L, Gall J, Bloom B, Falck-Pedersen E
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx NY, USA.
Gene Ther. 1996 Feb;3(2):154-62.
Adenovirus-mediated gene transfer experiments have demonstrated an exceptional efficiency of virus uptake and gene expression in a variety of in vivo models. Unfortunately, the efficiency of gene delivery is not accompanied by long-term gene expression. Maximal gene expression peaks during the first week of infection followed by a rapid decline to near baseline levels within several weeks. Data from several laboratories implicate host cellular and humoral immune responses as being responsible for the limited duration of expression and for the inability to successfully readminister a gene using adenovirus vectors. In this study we have examined two strategies which, independently or in combination, circumvent aspects of the host immune response against adenovirus-mediated gene therapy. The first strategy explores induction of immune tolerance in the experimental host as a method to increase the duration of gene expression and as a method to allow readministration of adenovirus expression vectors. Our second strategy is directed at the need to readminister adenoviral vectors to immune competent adult animals. We have demonstrated that a sequential exposure of rats to at least two other adenovirus serotypes does not compromise our ability to successfully administer an Ad5-based CAT expression vector. The characterization of serotype-specific neutralizing response indicates that the construction and use of Ad expression vectors from different serotypes will facilitate a useful adenovirus-based strategy allowing multiple administrations of a target gene.
腺病毒介导的基因转移实验已证明，在多种体内模型中，病毒摄取和基因表达效率极高。遗憾的是，基因递送效率并未伴随长期基因表达。感染第一周基因表达达到峰值，随后在数周内迅速降至接近基线水平。多个实验室的数据表明，宿主细胞和体液免疫反应是导致表达持续时间有限以及无法使用腺病毒载体成功再次给药基因的原因。在本研究中，我们考察了两种策略，它们单独或联合使用可规避宿主针对腺病毒介导的基因治疗的免疫反应。第一种策略是在实验宿主中诱导免疫耐受，以此增加基因表达持续时间，并作为允许再次给予腺病毒表达载体的方法。我们的第二种策略针对的是向免疫功能正常的成年动物再次给予腺病毒载体的需求。我们已证明，大鼠依次接触至少两种其他腺病毒血清型不会影响我们成功给予基于Ad5的CAT表达载体的能力。血清型特异性中和反应的特征表明，构建和使用不同血清型的Ad表达载体将有助于制定一种有用的基于腺病毒的策略，从而能够多次给予靶基因。
