The treatment or prevention of
bleeding in patients with
hemophilia A relies on replacement
therapy with different
factor VIII (FVIII)-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, and activated
protein C-specific
serpins or gene therapy. The latter strategies are, however, hampered by the short clinical experience and potential adverse effects including the absence of tight temporal and spatial control of coagulation and the risk of uncontrolled insertional mutagenesis. Systemic delivery of
mRNA allows endogenous production of the corresponding encoded
protein. Thus, injection of
erythropoietin-encoding
mRNA in a
lipid nanoparticle formulation resulted in increased erythropoiesis in mice and macaques. Here, we demonstrate that a single injection of in vitro transcribed B domain-deleted FVIII-encoding
mRNA to FVIII-deficient mice enables endogenous production of pro-
coagulant FVIII. Circulating FVIII:C levels above 5% of normal levels were maintained for up to 72 h, with an estimated half-life of FVIII production of 17.9 h, and corrected the
bleeding phenotype in a tail clipping assay. The endogenously produced FVIII did however exhibit 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. The use of alternative
mRNA delivery systems and improved FVIII-encoding
mRNA should foster the production of functional molecules and reduce their immunogenicity.