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Correction of bleeding in experimental severe hemophilia A by systemic delivery of factor VIII-encoding mRNA.

Haematologica 2019 July 10
The treatment or prevention of bleeding in patients with hemophilia A rely on replacement therapy with different factor VIII containing products or on the use of by-passing agents, i.e., activated prothrombin complex concentrates or recombinant activated factor VII. Emerging approaches include the use of bispecific anti-factor IXa/factor X antibodies, anti-Tissue Factor Pathway Inhibitor antibodies, interfering RNA to antithrombin, APC-specific serpins or gene therapy. The latter strategies however meet with short term clinical experience and potential adverse effects including the absence of tight temporal and spatial control of coagulation or risk for uncontrolled insertional mutagenesis. The systemic delivery of mRNA allows the endogenous production of the corresponding encoded protein. Thus, injection of lipid nanoparticles-formulated erythropoietin-encoding mRNA resulted in increased erythropoiesis in mice and macaques. Here, we demonstrate that a single injection of in vitro transcribed B domain-deleted factor VIII-encoding mRNA to factor VIII-deficient mice allows the endogenous production of pro-coagulant factor VIII. Circulating FVIII:C levels above 5% of normal levels were maintained for up to 72 hours, with an estimated half-life of factor VIII production of 17.9 hours, and corrected the bleeding phenotype in a tail clipping assay. The endogenously produced factor VIII however exhibited low specific activity and induced a potent neutralizing IgG response upon repeated administration of the mRNA. Our results suggest that the administration of mRNA is a plausible strategy for the endogenous production of proteins characterized by poor translational efficacy. At term, the use of alternative mRNA delivery systems and improved factor VIII-encoding mRNA should foster the production of functional molecules and reduce their immunogenicity.

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