Animal Models of Hemophilia

Abstract

The X-linked bleeding disorder hemophilia is caused by mutations in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Unless prophylactic treatment is provided, patients with severe disease (less than 1% clotting activity) typically experience frequent spontaneous bleeds. Current treatment is largely based on intravenous infusion of recombinant or plasma-derived coagulation factor concentrate. More effective factor products are being developed. Moreover, gene therapies for sustained correction of hemophilia are showing much promise in pre-clinical studies and in clinical trials. These advances in molecular medicine heavily depend on availability of well-characterized small and large animal models of hemophilia, primarily hemophilia mice and dogs. Experiments in these animals represent important early and intermediate steps of translational research aimed at development of better and safer treatments for hemophilia, such a protein and gene therapies or immune tolerance protocols. While murine models are excellent for studies of large groups of animals using genetically defined strains, canine models are important for testing scale-up and for longer-term follow-up as well as for studies that require larger blood volumes.

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

“…[87][88][89] Characterization of FVIII-specific T-cell clones and lines, and their use in studies exploring cell-based immunotherapies to promote immune tolerance to FVIII, are suggesting novel approaches to reduce the incidence of inhibitors. 90,91 Animal models remain essential for mechanistic studies, 92 and preclinical examination has demonstrated potential immune-regulatory properties of Fc fusion proteins 93 and the possible mitigation of FVIII immunogenicity with the long-term persistence of circulating FVIII levels achieved by gene transfer either alone 94 or through the generation of T-regulatory cells. 95 …”

Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation

“…In mouse models of various forms of hemophilia, no blood-filled lymphatic phenotypes have been reported. 52 These mice may have an intermediate phenotype, similar to the b 3 knockout mice, that is less obvious and escaped observation. However, lymphovenous hemostatic clots, which are small and function alongside valves, may simply not require thrombin activity to maintain blood/lymph separation.…”

Suppression of inhibitor formation against FVIII in a murine model of hemophilia A by oral delivery of antigens bioencapsulated in plant cells

“…4 Although there are currently no prophylactic protocols against inhibitor formation in patients, preclinical experiments in murine models of hemophilia A have provided proof of principle that preventive immune tolerance to FVIII can be established. [6][7][8][9][10][11] However, such protocols use genetic manipulation or immune suppressive drugs, raising safety concerns for translation to human treatment. In contrast, oral tolerance could be a more readily acceptable form of prophylactic tolerance induction and may be more readily tested in clinical trials.…”