Therapeutic approaches for haemophilia

The life-long episodic bleeding associated with inherited deficiencies of b lood coagulation Factor VIII (FVIII) or Factor IX (FIX) can be well control led with periodic iv. injections of FVIII or FIX concentrates. Either conce ntrate can be isolated from large human pools (i.e., plasma-derived FVIII o r FIX concentrate) or from culture supernatants of recombinant cells engine ered to secrete FVIII or FIX. The validated viral inactivation strategies u sed by manufacturers of FVIII and FIX concentrates have essentially elimina ted the transmission of hepatitis B, hepatitis C and HIV viruses. The low y ields 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 strat egies have been adopted and proposed to improve yields of FVIII. These incl ude: deletion of portions of FVIII which are not associated with function; mutations to prevent inactivation of FVIII by protease degradation; and syn thesis of FVIII fragments to replace portions deleted in some FVIII deficie nt patients. An approach to improve FIX replacement involves the production of more coagulatively active FIX mutants. Another promising approach in bo th FVIII and FIX replacement is gene therapy. Two major issues that will ha ve to be critically addressed before gene therapy for haemophilia can becom e widespread are whether the procedures will be well-tolerated in patients with significant liver impairment (due to previous exposure to hepatitis vi ruses) and whether consistent long-term delivery of the transgenes can be a chieved.