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      Evaluation of adeno-associated viral vectors for liver-directed gene transfer in dogs.

      Human Gene Therapy

      Animals, Dependovirus, genetics, Dogs, Gene Transfer Techniques, Genetic Vectors, Green Fluorescent Proteins, metabolism, Hepatic Artery, Liver, blood supply, T-Lymphocytes, Cytotoxic

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          Abstract

          This study evaluated six adeno-associated viral (AAV) vectors expressing green fluorescent protein (GFP) from the liver-specific thyroid hormone-binding globulin (TBG) promoter made with novel capsids in canine liver-directed gene transfer. Studies in 1.5-month-old dogs, which were administered vector through a peripheral vein, showed that AAV8 capsid vectors had the most favorable performance profiles. Interestingly, the absolute levels of hepatocyte transduction achieved with AAV8 were lower in dogs compared with what had been achieved in mice and nonhuman primates. Additional studies were performed with AAV8 delivered into the hepatic artery in adult dogs, with higher doses of vector used to assess potential dose-limiting toxicities. These studies showed good transduction on day 7 in one dog that apparently was lost by day 28 in another dog through the generation of GFP-specific T cells. Each adult dog was carefully monitored for any hemodynamic changes associated with vector infusion. Both animals demonstrated mild to moderate hypotension and bradycardia, which appeared to be anesthesia-related, making it difficult to evaluate contributions of the vector.

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          Journal
          21204705
          3159528
          10.1089/hum.2010.194

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