Therapeutic approaches for haemophilia

The life-long episodic bleeding associated with inherited deficiencies of blood coagulation Factor VIII (FVIII) or Factor IX (FIX) can be well controlled with periodic iv. injections of FVIII or FIX concentrates. Either concentrate can be isolated from large human pools (i.e., plasma-derived FVIII or FIX concentrate) or from culture supernatants of recombinant cells engineered to secrete FVIII or FIX. The validated viral inactivation strategies used by manufacturers of FVIII and FIX concentrates have essentially eliminated the transmission of hepatitis B, hepatitis C and HIV viruses. The low yields and inherent instability of FVIII (and FVIIIa in particular) and the additional costs of viral inactivation methods make the annual cost/patient for prophylaxis and treatment of haemophilia very expensive. Several strategies have been adopted and proposed to improve yields of FVIII. These include: deletion of portions of FVIII which are not associated with function; mutations to prevent inactivation of FVIII by protease degradation; and synthesis of FVIII fragments to replace portions deleted in some FVIII deficient patients. An approach to improve FIX replacement involves the production of more coagulatively active FIX mutants. Another promising approach in both FVIII and FIX replacement is gene therapy. Two major issues that will have to be critically addressed before gene therapy for haemophilia can become widespread are whether the procedures will be well-tolerated in patients with significant liver impairment (due to previous exposure to hepatitis viruses) and whether consistent long-term delivery of the transgenes can be achieved.