Online Issues

Journal Vol 50 (2)

Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

Timothy C. Nichols, Aaron M. Dillow, Helen W.G. Franck, Elizabeth P. Merricks, Robin A. Raymer, Dwight A. Bellinger, Valder R. Arruda, and Katherine A. High

Timothy C. Nichols, MD, is a professor; Aaron M. Dillow, BS, is a research specialist; Helen W.G. Franck, BS, is a research technician; Elizabeth P. Merricks, BS, and Robin A. Raymer, BS, are research specialists (advanced), and Dwight A. Bellinger, DVM, PhD, is a professor, all in the Department of Pathology and Laboratory Medicine at the University of North Carolina at Chapel Hill. Dr. Nichols is also a professor in the UNC-Chapel Hill Department of Medicine. Valder R. Arruda, MD, PhD, is an associate professor and Katherine A. High, MD, is a professor in the Department of Pediatrics at the University of Pennsylvania School of Medicine and the Children’s Hospital of Philadelphia, where Dr. High is also in the Howard Hughes Medical Institute.

Address correspondence and reprint requests to Dr. Timothy C. Nichols, Francis Owen Blood Research Laboratory, Department of Pathology and Laboratory Medicine, UNC School of Medicine CB#3114, 125 University Lake Road, Chapel Hill, NC 27516-3114 or email tnichols@med.unc.edu.

Abstract

Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders.

Key Words: coagulation assays; dog model; hemophilia; factor VII; factor VIII; factor IX; von Willebrand disease; von Willebrand factor