Treatment Option of Inherited Hemophilia A and B: In Case of Gene Therapy

Abstract

Hemophilia is the X-linked inherited bleeding illness caused by genetic abnormalities in the F8 (hemophilia A) or F9 (hemophilia B) genes. Hemophiliacs experience bleeding episodes into the joints and soft tissues, which can be managed with self-infusion of concentrations of factor VIII or IX. Because hemophilia is a monogenic illness with easily measured outcomes (factor levels and bleed rates), it makes it a desirable target for gene therapy. One of the most promising vectors for hemophilia gene therapy is lentiviral or adeno-associated virus (AAV)-based. Recombinant adeno-associated viral (AAV) vectors have been used successfully in all preclinical and clinical trials to far for factor VIII or IX hepatocyte transduction. These vectors were used to repair the bleeding phenotype in preclinical animal models of hemophilia A and B. Clinical translation to individuals with severe hemophilic phenotype was spurred by some of these encouraging preclinical results. This represents a significant advancement in the field because these patients undergoing gene therapy with AAV vectors demonstrated long-term expression of therapeutic FIX levels. With gene therapy, hemophilia patients can have a single treatment and maintain their factor levels for years or decades rather than relying on a steady supply of medication and frequent delivery at short intervals. Over the past ten years, significant progress has been achieved in the development of gene therapy for hemophilia. The phase III trial stage of adeno-associated virus (AAV) vector-mediated gene transfer in hemophilia A and B has begun. Clinical trials are currently evaluating factor VIII (FVIII) or factor IX (FIX) gene editing technologies or lentiviral vector gene transfer. It is anticipated that major markets will authorize and distribute the first gene therapy drugs, FVIII and FIX, in the near future.