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Review
. 2009;50(2):144-67.
doi: 10.1093/ilar.50.2.144.

Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency

Timothy C Nichols  1 , Aaron M Dillow, Helen W G Franck, Elizabeth P Merricks, Robin A Raymer, Dwight A Bellinger, Valder R Arruda, Katherine A High
Affiliations
Review

Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency

Timothy C Nichols et al. ILAR J. 2009.

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.

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Figures

Figure 1
Figure 1. Coagulation cascade
The extrinsic or cellular injury pathway is mediated by the binding of F.VIIa to tissue factor (TF) and the TF:F.VIIa complex in turn activates both F.X and F.IX. In the intrinsic or contact system, coagulation is initiated through high-molecular-weight kininogen (HMWK), prekallikrein (PK), and F.XII activation, which in turn activates F.XI, which then activates F.IX. F.VIIIa functions as a cofactor and significantly accelerates activation of F.X to F.Xa by F.IXa. Once activated, F.Xa participates in the prothrombinase complex (F.Xa:F.Va), which, in the presence of calcium (Ca2+) and phospholipids (PL), converts prothrombin (F.II) to thrombin. The latter, in turn, cleaves fibrinogen to soluble fibrin monomers that are cross linked by F.XIIIa to form a hemostatic plug or clot. Deficiency of F.VIII (hemophilia A) or F.IX (hemophilia B) results in impaired activation of F.X and downstream activation of thrombin and fibrin formation. Black arrow = conversion or activation of factor or cofactor function; red arrows = action of inhibitors; purple arrows = various functions of thrombin. TFPI, tissue factor pathway inhibitor.
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