FACTORS IMPEDING EFFICIENT EXPRESSION OF FACTOR-VIII COMPLEMENTARY-DNA MINIGENES

Haemophilia A is a bleeding disorder that affects approximately 1 in 1 0000 males. It is caused by a deficiency of functional blood-clotting factor VIII. Protein-replacement therapy has been effective as treatme nt, resulting in a vast improvement in the quality of life and dramati cally increasing the life expectancy of patients. However, therapy wit h plasma-derived factor VIII has allowed the transmission of several h uman viruses, such as hepatitis viruses, human immunodeficiency virus and parvovirus B19. To date, the safety of the therapeutic agent is on e of the key issues in haemophilia A treatment. The use of recombinant factor VIII in haemophilia therapy can avoid the dependence on blood- derived products and prevent the occurrence of transfusion-associated infections with blood-borne pathogens. Gene therapy could go further, and offers the prospect of one-time treatment which may, optimally, ac hieve a total cure of the disease. Therefore, haemophilia is an appeal ing and challenging target for somatic-cell gene therapy. On the basis of the phenotypic correction that is achieved upon infusion of factor VIII protein, it is expected that an increase in the factor VIII plas ma level to 10% of the level found in healthy individuals would suffic e to prevent the manifestation of the bleeding tendency. In this paper , we review the progress and the problems of gene therapy for haemophi lia, with special focus on the problems specifically associated with t he transfer and expression of human factor VIII complementary DNA.