With respect to the inefectivity of ITI in inducing a tolerance this website in as many as in 20–40% of inhibitor patients and the limitations of haemostatically ‘non-specific’

bypassing agents, inhibitors have been considered to be a most challenging complication of current haemophilia therapy [9]. To overcome the barriers to optimal treatment the current research is focused on the production of bioingeneered clotting factors with improved quality in terms of prolonged biological efficacy to obviate frequent administration, and reduced antigenicity/immunogenicity to mimize the inhibitor development [15]. Strategies being applied to FVIII include modifications of FVIII molecule such as the addition of polyethylene glycol (PEG) polymers and polysialic acids and alternative formulation with PEG-modified liposomes [15]. The last aproach has been used to produce BAY 79-4980, which was proved to prolong the bleeding free period in the phase I studies [16]. The phase II study presently being Luminespib chemical structure carried out in 62 centres in 14 different countries

will provide important information on the long-term safety and efficacy of this new drug. [13]. Other strategies not yet in clinical trial include genetic modifications of FVIII to extend the half life 上海皓元医药股份有限公司 after infusion [17]. The research on longer-acting PEGylated recombinant factor VIIa (FVIIa) showed the ability to activate factor X on tissue factor expressing cells, while its uptake was reduced

[18]. Despite the ultimate cure of haemophilia by gene therapy has not been reached yet, significant progress has been made in this field. To cure haemophilia a long-term expression of donated gene is necessary. To achieve this goal the transgene may be introduced into a stem cells or into a long-lived postmitotic cell, such as muscle cells, nerve cells or hepatocytes. For the gene transfer several strategies have been studied, employing retroviral vectors, plasmid transfection of autologous fibroblasts, infusion of adenoviral vectors or adeno-associated viral (AAV) vectors [19]. Promising results have been achieved with AAV vector delivery to the liver for factor IX (FIX), FVIII and FVIIa genes in animal models [20]. Continuous expression of therapeutic levels of bioingeneered FVIIa achieved by the gene transfer with AAV vector via portal vein in the haemophilic dogs promise an improved treatment for inhibitor patients obviating very short half life of recombinant FVIIa. It may offer an attractive alternative to haemostatic therapy also for non-inhibitor patients avoiding potential immunological challenges of FVIII gene therapy [20].