Recent advances in the understanding of the molecular biology of hemophilia A: possible implications towards a more effective therapeutic regime.

Hemophilic care was revolutionized in the late 50's, when factor VIII (FVIII) substitution therapy became accessible. Since then, plasma-derived FVIII preparations with varying degrees of purity have been widely used. The availability of such products has resulted in a great improvement of life quality and life expectancy of affected people. However, FVIII concentrates have been involved in the transmission of blood borne viruses like HIV and HCV. The tremendous development of molecular biology techniques, in association with modern biotechnology has allowed the large-scale production of first generation biopharmaceuticals such as recombinant FVIII, for clinical purposes. In parallel, intense research has revealed the genetic basis of hemophilia A, many aspects of FVIII biosynthesis and the biological function of FVIII. Synergistic efforts between genetic engineering and biotechnology have the potential to develop second generation products and therapeutic strategies based solely on "protein engineering". Integration of basic research results in new treatment concepts should allow the rational design of FVIII molecules endowed with improved functional properties. Such molecules may be highly beneficial in the development of future strategies in FVIII inhibitor therapy and in FVIII somatic gene therapy.