title: Adeno-associated viral vector serotype 5 poorly transduces liver in rat models.
abstract: Preclinical studies in mice and non-human primates showed that AAV serotype 5 provides efficient liver transduction and as such seems a promising vector for liver directed gene therapy. An advantage of AAV5 compared to serotype 8 already shown to provide efficient correction in a phase 1 trial in patients suffering from hemophilia B, is its lower seroprevalence in the general population. Our goal is liver directed gene therapy for Crigler-Najjar syndrome type I, inherited severe unconjugated hyperbilirubinemia caused by UGT1A1 deficiency. In a relevant animal model, the Gunn rat, we compared the efficacy of AAV 5 and 8 to that of AAV1 previously shown to be effective. Ferrying a construct driving hepatocyte specific expression of UGT1A1, both AAV8 and AAV1 provided an efficient correction of hyperbilirubinemia. In contrast to these two and to other animal models AAV5 failed to provide any correction. To clarify whether this unexpected finding was due to the rat model used or due to a problem with AAV5, the efficacy of this serotype was compared in a mouse and two additional rat strains. Administration of an AAV5 vector expressing luciferase under the control of a liver specific promoter confirmed that this serotype poorly performed in rat liver, rendering it not suitable for proof of concept studies in this species.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Montenegro-Miranda
authors.affiliation: Centro de Investigación Medica Aplicada (CIMA), Pamplona, Navarra, Spain.
authors.forename: Astrid
authors.initials: A
authors.lastname: Pañeda
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Lysbeth
authors.initials: L
authors.lastname: ten Bloemendaal
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Duijst
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Dirk R
authors.initials: DR
authors.lastname: de Waart
authors.affiliation: Centro de Investigación Medica Aplicada (CIMA), Pamplona, Navarra, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez- Aseguinolaza
authors.affiliation: Centro de Investigación Medica Aplicada (CIMA), Pamplona, Navarra, Spain.
authors.forename: Gloria Gonzalez
authors.initials: GG
authors.lastname: Aseguinolaza
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Piter J
authors.initials: PJ
authors.lastname: Bosma
mesh_terms: D000818:Animals; D000229:Dependovirus; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000821:virology*; D051381:Rats; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme