NON-CONVENTIONAL THERAPEUTIC STRATEGIES FOR INHERITED DISORDERS OF HEMOSTASIS

We propose to investigate a novel therapeutic approach for inherited coagulation deficiencies of factor VII and factor IX (Hemophilia B). The autosomally inherited FVII deficiency is rare whereas the X-linked hemophilia B affects 1/35000 males. The conventional substitutive treatment is able to prevent the life threatening and disabling bleeding episodes in the majority of patients with these deficiencies but is still associated with serious complications. Our approach is aimed at partially restoring coagulation function in the clinically severe form caused by nonsense mutations that we have previously identified. The therapeutic tool is offered by antibiotics found to prevent, with variable efficiency, premature termination of protein synthesis on ribosome. We plan to study cellular and animal models of the hemophilia B relatively more frequent nonsense mutations, that will permit a quantitative comparison of restored protein synthesis and coagulation function. The antibiotic-based therapeutic approach has produced positive results at the cellular level for the two factor VII nonsense mutations previously identified, for which the animal model is hardly feasible. We plan to measure, in the only two patients affected by these mutations, plasma factor VII levels and coagulation function after treatment with an antibiotic usually used for paediatric therapy. This research proposes an individually oriented therapeutic approach, potentially representing a lifesaving and cheap treatment when conventional management is not feasible. This strategy could be extended to other coagulation disorders.