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In vivo intranasal delivery of coagulation factor IX: a proof-of-concept study.
Journal of Thrombosis and Haemostasis : JTH 2023 August 25
BACKGROUND: Haemophilia B (HB) is a bleeding disorder characterised by coagulation factor IX (FIX) deficiency. The current standard-of-care for severe HB is prophylaxis with long-term repetitive intravenous (IV) infusions of recombinant FIX (rFIX) with standard half-life (SHL-rFIX) or extended half-life (EHL-rFIX). Unmet needs remain regarding the development of non-invasive administration routes for coagulation factors. The aim of this study was to evaluate the effectiveness of intranasal delivery (IND) of rFIX and rFIX fused to Fc fragment (rFIX-Fc) in mice.
METHODS: Drops of rFIX and rFIX-Fc were deposited in the nostrils of wild-type (WT), FcRn knock-out (FcRn KO), FcRn humanised (hFcRn), and FIX KO mice. rFIX mucosal uptake was evaluated by measuring plasma FIX antigen (FIX:Ag) and FIX activity (FIX:C) levels, and by performing histological analysis of the nasal mucosa following IND.
RESULTS: After IND, both rFIX and rFIX-Fc were equally delivered to the blood compartment, irrespective of the mouse strain studied, mostly through a passive mechanism of transportation across the mucosal barrier, independent of FcRn receptor. Both FIX:Ag and FIX:C activity levels were increased following IND in FIX KO mice.
CONCLUSION: This proof-of-concept study describes evidence supporting the nasal route as an alternative to FIX IV infusion for the treatment of HB.
METHODS: Drops of rFIX and rFIX-Fc were deposited in the nostrils of wild-type (WT), FcRn knock-out (FcRn KO), FcRn humanised (hFcRn), and FIX KO mice. rFIX mucosal uptake was evaluated by measuring plasma FIX antigen (FIX:Ag) and FIX activity (FIX:C) levels, and by performing histological analysis of the nasal mucosa following IND.
RESULTS: After IND, both rFIX and rFIX-Fc were equally delivered to the blood compartment, irrespective of the mouse strain studied, mostly through a passive mechanism of transportation across the mucosal barrier, independent of FcRn receptor. Both FIX:Ag and FIX:C activity levels were increased following IND in FIX KO mice.
CONCLUSION: This proof-of-concept study describes evidence supporting the nasal route as an alternative to FIX IV infusion for the treatment of HB.
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