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Novel recombinant proteins based on ancestral sequence reconstruction with higher specific activity than human vWF
About
Von Willebrand factor (vWF) is a multimeric blood glycoprotein with a monomeric size of ~250 kilodaltons. vWF plays a major role in hemostasis. It exerts its function by binding to other proteins, in particular factor VIII, and it is important in platelet adhesion to wound sites. Factor VIII is bound to vWF in the circulation with a half-life of up to 12 hours but without this binding it is rapidly degraded with a reduced half-life of 1-2 hours. Defects in vWF lead to the bleeding disorder von Willebrand disease (VWD), which is characterized by mucosa-associated bleeding and bleeding due to trauma or surgery. VWD is is subdivided into types 1, 2, and 3. Patients with type 1 VWD have blood levels of vWF of 20%-50% of normal and represent up to 80% of all VWD patients. Symptoms are mild. Type 2 VWD patients have functional defects in vWF due to missense mutations and represent between 15%-30% of all VWD patients. Type 2 is broken down into four subtypes: type 2A, type 2B, type 2M and type 2N, depending on the presence and behaviour of multimers, molecular chains of VWF. Symptoms are mild to moderate. Finally, type 3 VWD is a severe deficiency and is usually caused by genetic defects in the vWF gene leading to homozygous or compound heterozygous vWF null alleles. Type 3 patients represent
Key Benefits
1. Biochemical improvements as listed above will translate into a longer lasting more efficacious vWF therapy 2. Potential to add to Factor VIII for improved treatment of hemophilia 3. Flexible treatment modalities - can be given as a recombinant protein therapeutic or as a gene therapy
Applications
1. Von Willebrand Disease: type I, III and 2N VWD 2. Potentially Hemophilia A