title: Improvement of Adeno-Associated Virus-Mediated Liver Transduction Efficacy by Regional Administration in Macaca fascicularis.
abstract: The liver is a central organ in metabolism and can be affected by numerous inherited metabolic disorders. Recombinant adeno-associated virus (AAV)-based gene therapy represents a promising therapeutic approach for such diseases. AAVs have been demonstrated to be safe, and resulted in high and long-term expression in preclinical and clinical studies. However, there are still some concerns regarding the expression levels that can be achieved and the percentage of hepatocytes that can be transduced. Because of the cell-autonomous nature of most metabolic liver disorders, a high percentage of hepatocytes needs to be corrected in order to achieve a therapeutic effect. The goal of our work was to improve transduction efficacy of the liver by conveying the vector directly to hepatic tissue. Interventional radiology procedures were used to administer an AAV5 vector expressing a secreted form of human embryonic alkaline phosphatase (hSEAP) under the control of a liver-specific promoter to a clinically relevant animal model, Macaca fascicularis. Balloon occlusion of the regional hepatic venous flow was performed while injecting the vector either into the hepatic artery (HA) or, against flow, via the suprahepatic vein (SHV). In both cases the vector was injected into the right hepatic lobules, and the two routes were compared with conventional intravenous administration. Higher hSEAP levels were obtained when the vector was administered via SHV or HA than after intravenous injection. Furthermore, higher expression levels correlated with a higher number of vector genomes in the injected lobules. In conclusion, direct administration of AAV vectors via the hepatic blood flow with simultaneous balloon occlusion of the hepatic outflow increases liver transduction efficacy in comparison with systemic delivery and can be further improved in bigger animals or humans, where it would be technically feasible to inject the vector into the hepatic vasculature in the generality of lobules.
authors.affiliation: 1 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra (IdisNA) , Pamplona, Spain .
authors.forename: Nerea
authors.initials: N
authors.lastname: Zabaleta
authors.affiliation: 1 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra (IdisNA) , Pamplona, Spain .
authors.forename: David
authors.initials: D
authors.lastname: Salas
authors.affiliation: 2 Radiology Department, Clínica Universidad de Navarra, IdisNA, Pamplona, Spain .
authors.forename: Maria
authors.initials: M
authors.lastname: Paramo
authors.affiliation: 1 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra (IdisNA) , Pamplona, Spain .
authors.forename: Mirja
authors.initials: M
authors.lastname: Hommel
authors.affiliation: 3 uniQure, Amsterdam, the Netherlands .
authors.forename: Valerie
authors.initials: V
authors.lastname: Sier-Ferreira
authors.affiliation: 1 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra (IdisNA) , Pamplona, Spain .
authors.forename: Ruben
authors.initials: R
authors.lastname: Hernandez-Alcoceba
authors.affiliation: 1 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra (IdisNA) , Pamplona, Spain .
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.affiliation: 2 Radiology Department, Clínica Universidad de Navarra, IdisNA, Pamplona, Spain .
authors.forename: Jose I
authors.initials: JI
authors.lastname: Bilbao
authors.affiliation: 1 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra (IdisNA) , Pamplona, Spain .
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez-Aseguinolaza
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008252:Macaca fascicularis; D011401:Promoter Regions, Genetic; D014161:Transduction, Genetic
chemical_list: D000469:Alkaline Phosphatase
keywords: IND-enabling studies; adeno-associated virus; clinical development; delivery methods; disease models; liver; metabolic; vectors