Gene Therapy for Hemophilia B: Aav-Mediated Transfer of The Gene for Coagulation Factor IX to Human Muscle

Abstract

Hemophilia B is an X-linked bleeding disorder caused by a deficiency of coagulation factor IX. In its severe form, the disease results in spontaneous bleeding as well as bleeding following surgery or trauma, and is clinically indistinguishable from hemophilia A (factor VIII deficiency). The major morbidity of the disease is the chronic arthropathy of hemophilia that develops following spontaneous hemorrhage into the joint spaces. Blood in the joint space serves as an irritant causing proliferation of the vascular synovial membranes. Hypertrophied synovium is more susceptible to injury resulting in a vicious cycle of rebleeding that furthers the destruction of the joint. The major bleeding-related mortality of hemophilia is intracranial hemorrhage that occurs in between 3 and 14% of patients (1–3). The mortality rate from intracranial hemorrhage ranges from 20–50%, and survivors are often left with severe neurological sequelae such as seizures, paresis or mental retardation (1). Current treatment of hemophilia is based on the episodic intravenous infusion of highly purified plasma-derived or recombinant clotting factor concentrates in response to bleeding episodes (on-demand therapy).