Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs.
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.
Jiang
Haiyan
H
Avigen, Almeda, CA, USA. haiyan.jiang.b@bayer.com
Lillicrap
David
D
Patarroyo-White
Susannah
S
Liu
Tongyao
T
Qian
Xiaobing
X
Scallan
Ciaran D
CD
Powell
Sandra
S
Keller
Tracey
T
McMurray
Morag
M
Labelle
Andrea
A
Nagy
Dea
D
Vargas
Joseph A
JA
Zhou
Shangzhen
S
Couto
Linda B
LB
Pierce
Glenn F
GF
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
D005169:Factor VIII