Ancestral variants of Factor VIII proteins with increased biosynthetic efficiency, specific activity, and stability as well as decrease immune reactivity for replacement therapy to treat patients with hemophilia A.
- Ancestral sequence-based factor VIII variants are functionally superior to human factor VIII in both protein replacement and gene therapy settings.
- Ancestral derived Factor VIII variants have increased pharmacological properties over current recombinant factor VIII products.
- Ancestral factor VIII variants display more efficient cellular biosynthesis that translates to improved manufacturing yields of recombinant factor VIII and higher levels of plasma factor VIII in gene therapy settings.
Hemophilia A is a rare bleeding disorder that occurs in 1 out of 5,000 male births. The disease results from various mutations in the F8 gene resulting in a deficiency of plasma FVIII activity and inability to form stable blood clots following vessel injury. Currently, hemophilia A patients are treated with factor VIII replacement products comprising either plasma derived or recombinant factor VIII. Despite their clinical effectiveness, current factor VIII products have severe limitation including cost, due to production efficiency, short circulating half-life and high incidence of anti-drug antibody formation. To date, no transformational advances in hemophilia A care have come about since the marketing of recombinant factor VIII in the early 1990's.
Drs. Doering and Gaucher have employed ancestral sequence reconstruction studies of the factor VIII cDNA and protein to identify ancestral variants of the coagulation factor with superior pharmaceutical properties. They have identified several recombinant ancestral factor VIII variants display both anticipated and unanticipated pharmacological property differentials including greater than 10-fold more efficient biosynthesis, 2 - 5-fold higher specific activity, 5 - 8-fold longer half-life following activation and reduced reactivity with anti-human factor VIII antibodies. These improvements may result in cheaper, more potent, longer-acting and less immune reactive therapeutics for the 400,000+ persons in the world living with hemophilia A.
Early stage proof of concept in vitro and in vivo studies show the potential benefits of certain ancestral factor VIII for protein replacement and gene therapy of hemophilia A.