Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency.
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.
Nichols
Timothy C
TC
Department of Pathology, Francis Owen Blood Research Laboratory, Laboratory Medicine at the University of North Carolina at Chapel Hill, NC 27516-3114, USA. tnichols@med.unc.edu
Dillow
Aaron M
AM
Franck
Helen W G
HW
Merricks
Elizabeth P
EP
Raymer
Robin A
RA
Bellinger
Dwight A
DA
Arruda
Valder R
VR
High
Katherine A
KA
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D005168:Factor VII Deficiency / Q000235:genetics / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006467:Hemophilia A / Q000235:genetics / Q000628:therapy*; D002836:Hemophilia B / Q000235:genetics / Q000628:therapy*; D016031:Liver Transplantation / Q000379:methods; D011506:Proteins / Q000008:administration & dosage*; D014842:von Willebrand Diseases / Q000235:genetics / Q000628:therapy*; D014841:von Willebrand Factor / Q000378:metabolism
D011506:Proteins; D014841:von Willebrand Factor