GENE THERAPY IN BABOONS

狒狒的基因治疗

• 批准号: 8357645
• 负责人: Philip Ng
• 金额: $ 14.48万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357645
• 关键词: Acute; Antibodies; Dose; Funding; Gene Transfer; Grant; Hepatocyte; Injection of therapeutic agent; Liver; Liver Circulation; Methods; National Center for Research Resources; Peripheral; Portal vein structure; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Safety; Source; Toxic effect; United States National Institutes of Health; Veins; cost; gene therapy; helper-dependent adenoviral vector; improved; prevent; transduction efficiency; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 由于该方法的简单性和无创性，通过注射到外周静脉的HDAD被广泛用于基因治疗的肝脏定向基因转移。 但是，为了实现有效的肝细胞转导，需要高剂量的载体，不幸的是导致严重的急性毒性。 通过直接向量注射到肝脏的门静脉中，试图避免这种障碍。但是，就毒性和肝细胞转导效率而言，结果与遵循外周静脉注射没有什么不同。 该项目的目的是确定仅通过在通过门静脉传递载体之前首先分离肝循环，将依赖辅助腺病毒载体传递到肝细胞基因转移的肝脏基因转移的可行性。 我们假设该策略将导致高效肝细胞转导使用显着较低的载体剂量，从而减少（如果不消除）急性毒性。 此外，控制肝脏循环的能力可以允许在存在已经存在的中和抗AD抗体的情况下有效转导，这对于后来的载体恢复至关重要，并防止载体的全身传播，这将进一步提高安全性。