Small antibody fragments as alternative tools in haemophilia care

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The functional absence of coagulation factor VIII (FVIII) is associated with a severe bleeding disorder, known as haemophilia A, affecting 1-2 per 10,000 males. Clinical management mainly involves replacement therapy using purified FVIII concentrates. Due to a number of disadvantages of this approach (frequent intravenous infusions, development of inhibitory antibodies, high costs), there is a strong medical need for the development of novel therapeutic strategies. The aim of the present project is to develop in parallel a low-cost protein therapy and an innovative AAV-based gene therapy approach for haemophilia A using single domain antibody fragments (nanobodies). Nanobodies have several advantages, including a low (if any) immunogenicity when applied to humans. Further, their small size (±17 kDa) facilitates their molecular engineering and the incorporation of their cDNA in viral particles. Nanobodies will be generated that target natural anticoagulants. Inhibition of these anticoagulants restores the defective thrombin generation capacity in haemophilic mice. Indeed, preliminary studies by one of the partners in our consortium have shown that such nanobodies fully restore thrombin generation in haemophilic plasma and reduce blood loss in haemophilic mice. In this research program, we will explore two different modes of nanobody delivery: protein administration and gene transfer. The first approach will focus on the development of subcutaneous delivery, leading to an improved low-cost treatment regimen. The second approach provides the potential of a long-term therapeutic solution to minimize bleeding in haemophilia.