32. Efficacy and Safety of Mouse Coagulation Factor VIIa Gene Transfer in Hemophilia B Mice

One major complication of replacement therapy with clotting factors in patients with hemophilia A and B is the development of inhibitory antibodies that neutralize and inactivate the administered protein. Infusion of recombinant human factor VIIa (NovoSeven) into hemophilic patients bypasses the ris...

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Veröffentlicht in:Molecular therapy 2004-05, Vol.9 (S1), p.S14-S14
Hauptverfasser: Aljamali, Majed N, Margaritis, Paris, Arruda, Valder R, Schlachterman, Alexander, Camire, Rodney M, High, Katherine A
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Sprache:eng
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Zusammenfassung:One major complication of replacement therapy with clotting factors in patients with hemophilia A and B is the development of inhibitory antibodies that neutralize and inactivate the administered protein. Infusion of recombinant human factor VIIa (NovoSeven) into hemophilic patients bypasses the risk of antibody formation and provides a successful alternative approach to achieving normal hemostasis. We generated a recombinant adeno-associated virus (AAV) vector delivering an engineered mouse factor VII gene under the control of liver-specific promoter. The gene product is cleaved intracellularly and secreted as an activated mFVIIa. The levels of mFVII, measured by our in house ELISA, were about two to three fold of the baseline in HB mice, four and eight weeks after AAV injection into their spleen. This was accompanied by shortening of clotting times measured in the plasma of these mice (PTs and aPTTs). Additionally, in vivo tail clip assay showed a partial correction of bleeding in AAV treated HB mice compared to non-treated HB mice. Thrombin-antithrombin (TAT) levels did not change significantly in the treated HB mice up to 6 months post injection at 1.2×1012 vg/mouse dose, although an increase was seen at a higher dose. The survival rate was also similar between the treated and non-treated HB mice. In a follow-up study, we have generated transgenic mice with a range of levels of mFVIIa to analyze levels of expression that afford optimal efficacy and safety. We conclude that elevated and effective levels of activated murine factor VII can be achieved by AAV-mediated, liver-directed transgene delivery. This novel approach improves hemostasis in hemophilic mice with apparently no risk for thrombosis at this dose.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2004.05.055