LIVER-EXCLUSIVE TRANSDUCTION WITH HDAD VECTORS FOR GENE THERAPY

用于基因治疗的 HDAD 载体的肝脏专属转导

• 批准号: 7716181
• 负责人: Philip Ng
• 金额: $ 0.71万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716181
• 关键词: Acute; Adenoviruses; Affect; Animals; Autopsy; Balloon Occlusion; Catheters; Computer Retrieval of Information on Scientific Projects Database; Disease; Dose; Effectiveness; Funding; Gene Transduction Agent; Gene Transfer; Grant; Hepatic; Hepatic artery; Hepatocyte; Human; Injection of therapeutic agent; Institution; Liver; Macaca mulatta; Methods; Organ; Papio; Peripheral; Portal vein structure; Positioning Attribute; Primates; Procedures; Range; Research; Research Personnel; Resources; Safety; Source; Testing; Toxic effect; United States National Institutes of Health; Veins; Venous; Veterinarians; Work; gene therapy; helper-dependent adenoviral vector; human disease; nonhuman primate; research study; vector

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. The liver is a very attractive target organ for gene therapy because it is the affected organ in many congenital and acquired diseases. Peripheral vein injection of an artificially modified adenovirus called helper-dependent adenoviral vector or HDAd has been widely employed for transferring genes to the liver cells. However, in order to achieve efficient gene transfer, 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 vessels directly serving the liver, the portal vein and the hepatic artery. However, the results, in terms of toxicity and efficiency of gene transfer, were no different than following peripheral vein injection. The objective of this project is to determine the feasibility of delivering helper-dependent adenoviral vectors preferentially to the liver for liver gene transfer by occluding the venous outflow from the liver prior to delivery of the vector via the hepatic artery, This strategy will allow trapping the vector within the liver thereby enhancing the efficiency of gene transfer to the liver cells. Hepatic venous outflow occlusion will be performed by inflating a balloon occlusion catheter percutaneously positioned and vector delivery will be accomplished by percutaneously positioning a catheter in the hepatic artery. We have shown previously that this strategy resulted in high efficiency of liver gene transfer using significantly lower vector doses and thus reduce acute toxicity in baboons. We wish to determine if this is also the ease in a different nonhuman primate species and have chosen the rhesus monkey. The combined results from the baboon and the rhesus monkey will be important in assessing safety and efficacy of our approach prior to human trials. Toxicity related to the procedure and vector will be assessed at predetermined intervals. We will also determine liver cell gene transfer efficiency. Duration of expression of the gene transferred to the liver cells and long-term toxicity will also be assessed. Before performing studies in humans, it is essential to test the safety and effectiveness of gene therapy vectors in animals. Primates are particularly important as a final step to assess safety prior to study of humans. Rhesus monkeys are chosen because they are a relatively feasible option for primate work. The animals will be sacrificed and necropsied at the end of the experiment using methods chosen by the veterinarian. These experiments should provide valuable information that may eventually allow the use of helper-dependent adenoviral vectors for treatments of a wide range of human diseases.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 肝脏是基因疗法的非常有吸引力的靶心器官，因为它是许多先天性和后疾病的受影响器官。人为修饰的腺病毒的外周静脉注射称为助手依赖性腺病毒载体或HDAD已广泛用于将基因转移至肝细胞。但是，为了实现有效的基因转移，需要高剂量的载体，不幸的是导致严重的急性毒性。 通过直接向量注入直接服务肝脏，门静脉和肝动脉的血管，试图绕过这一障碍。然而，就基因转移的毒性和效率而言，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在通过肝动脉递送载体之前从肝脏中遮挡肝脏流出的静脉流出来确定肝脏基因转移肝脏基因转移的可行性，该策略将允许在肝脏中捕获载体，从而使载体在基因转移的效率内诱捕载体。肝静脉流出的闭塞将通过膨胀的气球闭塞导管经皮膨胀，并通过将导管在肝动脉中固定定位来实现。我们先前已经表明，这种策略使用明显较低的载体剂量导致了肝基因转移的高效率，从而降低了狒狒的急性毒性。我们希望确定这是否也是不同人类灵长类动物中的轻松，并选择了恒河猴。狒狒和恒河猴的综合结果对于在人类试验之前评估我们方法的安全性和功效至关重要。与程序和载体有关的毒性将以预定的间隔进行评估。我们还将确定肝细胞基因转移效率。也将评估转移到肝细胞的基因表达持续时间和长期毒性。 在对人类进行研究之前，必须测试动物基因治疗载体的安全性和有效性。灵长类动物在研究人类之前评估安全性的最后一步尤其重要。之所以选择恒河猴，是因为它们是灵长类动物工作的相对可行的选择。这些动物将在实验结束时使用兽医选择的方法在实验结束时处置和死灵。 这些实验应提供有价值的信息，这些信息最终可能允许使用辅助腺病毒载体来治疗多种人类疾病。