title: Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.
abstract: Severe hemophilia A (HA) is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII) clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Callan
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.affiliation: Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004283:Dog Diseases / Q000235:genetics* / Q000628:therapy*; D004285:Dogs / Q000235:genetics*; D005169:Factor VIII / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006467:Hemophilia A / Q000235:genetics / Q000628:therapy / Q000662:veterinary*; D008297:Male; D057805:Pets / Q000235:genetics; D010641:Phenotype
chemical_list: D005169:Factor VIII