Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs

• Published in: Blood 2006-07, Vol.108 (1), p.107-115
• Main Authors: Jiang, Haiyan, Lillicrap, David, Patarroyo-White, Susannah, Liu, Tongyao, Qian, Xiaobing, Scallan, Ciaran D., Powell, Sandra, Keller, Tracey, McMurray, Morag, Labelle, Andrea, Nagy, Dea, Vargas, Joseph A., Zhou, Shangzhen, Couto, Linda B., Pierce, Glenn F.
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Southern; Dogs; Factor VIII - administration & dosage; Factor VIII - genetics; Genetic Therapy - methods; Genetic Vectors - genetics; Hemophilia A - genetics; Hemophilia A - therapy; In Situ Hybridization, Fluorescence; Liver - blood supply; Liver - metabolism; Mice; Mice, Mutant Strains; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Serotyping; Thrombelastography
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-12-5115

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. (Blood. 2006;108:107-115)