This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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