Fieux Maxime, Rovera Renaud, Coiffier Céline, Colomb Evelyne, Enjolras Nathalie, Béquignon Emilie, Monge Claire, Le Quellec Sandra
Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d'ORL, d'otoneurochirurgie et de chirurgie cervico-faciale, F-69310, Pierre Bénite, France; Université de Lyon, Université Lyon 1, F-69003, Lyon, France; Univ Paris Est Créteil, INSERM, IMRB, F-94010 Créteil, France; CNRS EMR 7000, F-94010 Créteil, France.
UMR 5305, Laboratoire de Biologie Tissulaire et d'Ingénierie Thérapeutique, Institut de Biologie et Chimie des Protéines, CNRS/Université Claude Bernard Lyon 1, 7 Passage du Vercors, CEDEX 07, 69367 Lyon, France.
J Thromb Haemost. 2023 Nov;21(11):3117-3123. doi: 10.1016/j.jtha.2023.08.019. Epub 2023 Aug 25.
Hemophilia B (HB) is a bleeding disorder characterized by coagulation factor (F) IX (FIX) deficiency. The current standard-of-care for severe HB is prophylaxis with long-term repetitive intravenous (i.v.) infusions of recombinant FIX (rFIX) with standard half-life or extended half-life. 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.
Drops of rFIX and rFIX-Fc were deposited in the nostrils of wild-type, FcRn knock-out, FcRn humanized, and FIX knock-out mice. rFIX mucosal uptake was evaluated by measuring plasma FIX antigen and FIX activity (FIX:C) levels, and by performing histologic analysis of the nasal mucosa following IND.
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 plasma FIX antigen and FIX:C activity levels increased following IND in FIX knock-out mice.
This proof-of-concept study describes evidence supporting the nasal route as an alternative to FIX i.v. infusion for the treatment of HB.
B型血友病（HB）是一种以凝血因子（F）IX（FIX）缺乏为特征的出血性疾病。目前，重度HB的标准治疗方法是使用具有标准半衰期或延长半衰期的重组FIX（rFIX）进行长期重复静脉输注预防。凝血因子非侵入性给药途径的开发仍存在未满足的需求。本研究的目的是评估rFIX和与Fc片段融合的rFIX（rFIX-Fc）经鼻给药（IND）在小鼠中的有效性。
将rFIX和rFIX-Fc滴入野生型、FcRn基因敲除、FcRn人源化和FIX基因敲除小鼠的鼻孔。通过测量血浆FIX抗原和FIX活性（FIX:C）水平，并在IND后对鼻黏膜进行组织学分析，评估rFIX的黏膜摄取情况。
IND后，无论研究的小鼠品系如何，rFIX和rFIX-Fc均以相同方式进入血液循环，主要通过跨黏膜屏障的被动转运机制，且不依赖FcRn受体。在FIX基因敲除小鼠中，IND后血浆FIX抗原和FIX:C活性水平均升高。
这项概念验证研究描述了支持经鼻途径作为治疗HB替代FIX静脉输注的证据。
