title: Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs.
abstract: Hemophilia A, a deficiency of functional coagulation factor VIII (FVIII), is treated via protein replacement therapy. Restoring 1% to 5% of normal blood FVIII activity prevents spontaneous bleeding, making the disease an attractive gene therapy target. Previously, we have demonstrated short-term activity of a liver-specific AAV2 vector expressing canine B-domain-deleted FVIII (cFVIII) in a hemophilia canine model. Here, we report the long-term efficacy and safety of AAV-cFVIII vectors of serotypes 2, 5, 6, and 8 in both hemophilia A mice and dogs. AAV6-cFVIII and AAV8-cFVIII restored physiologic levels of plasma FVIII activity in hemophilia A mice. The improved efficacy is attributed to more efficient gene transfer in liver compared with AAV2 and AAV5. However, supraphysiologic cFVIII levels correlated with the formation of cFVIII-neutralizing antibodies in these mice. Of importance, hemophilia A dogs that received AAV2-cFVIII, AAV6-cFVIII, and AAV8-cFVIII have persistently expressed therapeutic levels of FVIII, without antibody formation or other toxicities, for more than 3 years. However, liver transduction efficiencies are similar between AAV2, AAV6, and AAV8 serotypes in hemophilia A dogs, in contrast to mice. In summary, this is the first report demonstrating multiyear therapeutic efficacy and safety of multiple AAV-cFVIII vectors in hemophilia A dogs and provides the basis for human clinical studies.
authors.affiliation: Avigen, Almeda, CA, USA. haiyan.jiang.b@bayer.com
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
authors.forename: Susannah
authors.initials: S
authors.lastname: Patarroyo-White
authors.forename: Tongyao
authors.initials: T
authors.lastname: Liu
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Qian
authors.forename: Ciaran D
authors.initials: CD
authors.lastname: Scallan
authors.forename: Sandra
authors.initials: S
authors.lastname: Powell
authors.forename: Tracey
authors.initials: T
authors.lastname: Keller
authors.forename: Morag
authors.initials: M
authors.lastname: McMurray
authors.forename: Andrea
authors.initials: A
authors.lastname: Labelle
authors.forename: Dea
authors.initials: D
authors.lastname: Nagy
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Vargas
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: Linda B
authors.initials: LB
authors.lastname: Couto
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Pierce
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D004285:Dogs; D005169:Factor VIII / Q000008:administration & dosage* / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006467:Hemophilia A / Q000235:genetics / Q000628:therapy*; D017404:In Situ Hybridization, Fluorescence; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D012703:Serotyping; D013916:Thrombelastography
chemical_list: D005169:Factor VIII