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Enhanced vWF sequences for recombinant protein delivery or gene therapy

Background

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 upto 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 <5% of all VWD patients. Symptoms are typically severe, and include spontaneous bleeding episodes, often into their joints and muscles. According to Orphanet annual incidence of type 3 VWD varies between countries ranging from 1/2,000,000 to 1/350,000 in Europe and the USA and with estimates of around 1/500,000 in countries where consanguinity is more frequent.

Technology Overview

Unlike other vWD patients – those with type 3 VWD do not respond to desmopressin and therefore substitution therapy with vWF is necessary. Historically this has been accomplished with plasma-derived vWF-containing concentrates. These concentrates have evolved from crude preparations of plasma proteins to plasma-derived concentrates containing both vWF and factor VIII.

However, some patients (7.5-9.5% of cases) develop alloantibodies against vWF rendering the substitution treatment ineffective and resulting in an anaphylactic response associated with the formation of immune complexes. In these cases, alternative treatments, such as continuous infusion of recombinant factor VIII or recombinant activated factor VII, are considered. Furthermore, the varying amounts and quality of these vWF concentrates, including the varying content of Factor VIII, have contributed to the lack of a standardized approach to replacement therapy. To try to overcome this lack of standardization a recombinant vWF drug, Vonvendi, was approved by the FDA in 2015. It has predicted global sales of $400-500 million USD.