GENE THERAPY IN BABOONS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。由于该方法简单且无创，经外周静脉全身注射HDAd已被广泛用于肝定向基因转移，以达到基因治疗的目的。然而，为了实现有效的肝细胞转导，需要高剂量的载体，这不幸导致严重的急性毒性。绕过这一障碍的尝试已经通过直接载体注射进入肝脏门静脉。然而，在毒性和肝细胞转导效率方面，结果与外周静脉注射没有什么不同。该项目的目的是确定通过门静脉输送载体之前，首先分离肝脏循环，将辅助依赖腺病毒载体完全输送到肝脏进行肝细胞基因转移的可行性。我们假设，这种策略将导致高效的肝细胞转导使用显著降低载体剂量，从而减少，如果不能消除，急性毒性。此外，控制肝脏循环的能力可能允许在预先存在的中和性抗ad抗体存在的情况下有效转导，这对后来的载体再给药很重要，并防止载体的全身传播，这将进一步提高安全性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Systemic delivery of HDAd by injection into a peripheral vein has been widely employed for liver-directed gene transfer for the purpose of gene therapy due to the method¿s simplicity and noninvasiveness. However, in order to achieve efficient hepatocyte transduction, high doses of vector are required which unfortunately result in severe acute toxicity. Attempts to circumvent this obstacle have been made by direct vector injection into the portal vein of the liver. However, the results, in terms of toxicity and hepatocyte transduction efficiency, were no different than following peripheral vein injection. The objective of this project is to determine the feasibility of delivering helper-dependent adenoviral vectors exclusively to the liver for hepatocyte gene transfer by first isolating the liver circulation prior to delivery of the vector via the portal vein. We hypothesize that this strategy will result in high efficiency hepatocyte transduction using significantly lower vector doses and thus reduce, if not eliminate, acute toxicity. Furthermore, the ability to control the liver circulation may permit efficient transduction in the presence of preexisting neutralizing anti-Ad antibodies, important for later vector readministration, as well as prevent systemic dissemination of the vector, which would further improve safety.