Журнал генетических синдромов и генной терапии
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Engineered Factor VII, Factor IX, and Factor X Variants for Hemophilia Gene Therapy

Patricia Quade-Lyssy, Peter Milanov and Jorg Sch?ttrumpf

The coagulation factors VII, IX, and X are all vitamin K dependent serine proteases synthesized in the liver with a high degree of similarity concerning size and structure. Factor IX is the deficient protein in hemophilia B and used in substitution therapy. The activated form of factor VII (FVIIa) is used to treat hemophilia in which the coagulant tenase complex cannot form due to inhibitory antibodies predominantly directed against factor VIII (FVIII) in hemophilia A. For both FVIIa and FIX, diverse approaches in protein engineering have been successfully applied to enhance protein activity, secretion, or half-life. Approaches include modification of functional important amino acid residues as well as the generation of fusion proteins. FX, on the other hand is the common substrate of both FVII as well as FIX. More recently, engineering of FX was therefore employed to shortcut FX activation by the physiological tenase complex, which is affected in both disorders, hemophilia A and B. All three proteases might therefore play a role in gene transfer strategies for hemophilia. In early clinical studies, the expression levels following gene transfer have been limited by dose dependent immune responses against the vector (AAV, liver-directed) or the therapeutic transgene (AAV, intramuscular). Therefore, protein modification might provide the necessary improvement to lift therapies in the therapeutic range while limiting vector exposure and local expression levels. Shifting gene transfer from FVIII to FVIIa or to variants of FVIIa, FIX or FX might additionally be a strategy to bypass inhibitory antibodies against FVIII and address limits of the vector packaging due to size limit restrictions encountered in FVIII gene transfer at the same time.