Moroctocog alfa

In hemophilia, deficiency of factor VIII or IX prevents the activation of the common coagulation pathway, and inhibits the conversion of FX to activated FXa, which is required for thrombin generation. We hypothesized that the direct expressed FXa has the potential to activate the common pathway and restore coagulation in hemophilia patients. In this study, the cassettes that expressed FXa, FXaop and FXa-FVII were packaged into an engineered AAV capsid, AAV843, and were delivered into hemophilia A and B mice by intravenous injection. AAV-FXaop could be stably expressed in vivo and showed the best immediate and prolonged hemostatic effects, similar to those of commercial drugs (Xyntha and Benefix). AAV-FXaop also significantly inhibited bleeding in hemophilia A mice with inhibitors. In addition, FXa expression in joints significantly alleviated the occurrence of hemophilic synovitis. AAV-delivered FXa may be a novel target for treating hemophilic and hemophilic synovitis.

IntroductionHereditary thrombotic thrombocytopenic purpura (hTTP) is caused by deficiency of plasma ADAMTS13 activity, resulting from ADAMTS13 mutations.ADAMTS13 cleaves ultra large von Willebrand factor (VWF), thus reducing its multimer sizes.Hereditary deficiency of plasma ADAMTS13 activity leads to the formation of excessive platelet-VWF aggregates in small arterioles and capillaries, resulting in hTTP.Areas coveredPubMed search from 1956 to 2024 using thrombotic thrombocytopenic purpura and therapy identified 3,675 articles.Only the articles relevant to the topic were selected for discussion, which focuses on pathophysiol., clin. presentations, and mechanisms of action of emerging therapeutics for hTTP.Current therapies include infusion of plasma, or coagulation factor VIII, or recombinant ADAMTS13.Emerging therapies include anti-VWF A1 aptamers or nanobody and gene therapies with adeno-associated viral vector or self-inactivated lentiviral vector or a sleeping beauty transposon system for a long-term expression of a functional ADAMTS13 enzyme.Expert opinionFrequent plasma infusion remains to be the standard of care in most parts of the world, while recombinant ADAMTS13 has become the treatment of choice for hTTP in some of the Western countries.The success of gene therapies in preclin. models may hold a promise for future development of these novel approaches for a cure of hTTP.