Biologics and nasal route : development and application in chronic rhinosinusitis with nasal polyps
BIOTHERAPIES et VOIE NASALE : développement et application dans la polypose nasosinusienne
Résumé
Background: Multiple biologics have been recently suggested as a new treatment for chronic
rhinosinusitis with nasal polyps (CRSwNP). Currently, only two drugs can be prescribed in France
(dupilumab and mepolizumab), as a second line treatment, in severe and not controlled CRSwNP despite
oral corticosteroids and sinus surgery, but the terms "severity" and "control" are not consensual.
CRSwNP is a type 2 inflammatory model? disease? and is also considered an epithelial dysregulation
model, for which the pathogenesis is not completely elucidated. The effect of biologics, at the cellular
level, on human nasal epithelial cells (HNEC) has not been explored and other therapeutic targets could
be considered. In addition, the subcutaneous route might be a limitation to the efficacy of these drugs.
Here, we focus on an ubiquitous receptor, the neonatal receptor for the crystallizable fragment (FcRn)
of Ig, which plays a key role in immunoglobulin (Ig) homeostasis. Fc-fused biologics ((Eftrenonacog
alfa, rFIX-Fc) exist for the treatment of hemophilia B (HB). This disease requires frequent intravenous
administration of factor IX (FIX) to prevent bleeding. The rFIX-Fc could be recognized by the FcRn
allowing intranasal delivery (IND).
Objective: The objective of this thesis was to : i/ set up a national clinical study (Polyposis Severity
Index, PSI study) to create a severity score for CRSwNP in silico based on clinical, biological and
radiological data; ii/ characterize in vitro the effects of OSM, IL-4, IL-13 and dupilumab on HNEC
(barrier function, ciliary beating efficiency and wound repair rate); and, iii/ evaluate in vivo the efficacy
of IND for biologics (rFIX-Fc), used in the treatment of HB in transgenic mouse models.
Methods: A prospective multicenter study was set up in France (NCT05056714). In order to build the
latent variable model linking the different indicators measured in patients to the latent severity of
CRSwNP (PSI score), structural equations will be generated. In a primary culture model of HNEC in
air-liquid interface, the effects of cytokines (IL-6, OSM, IL-4, and IL-13) and dupilumab on epithelial
functions (barrier function, ciliary beating efficiency and wound repair rate) were compared to control
conditions. Finally, an experimental research protocol on animals was set up to make the proof-ofconcept
that IND of rFIX-Fc is possible and to study the role of FcRn on transgenic mice models (FcRn
knock-out (KO), FIX KO, and FcRn humanized).
Results: To date, 417 patients have been included in the PSI study and we hope to quickly start the first
statistical modelling (as soon as n=470). In vitro, OSM, but not IL-6, induced a significant decrease in
barrier function and mucociliary clearance efficiency on HNEC. After 24 hours, the wound repair rate
(WRR) was significantly higher in OSM-stimulated HNEC. In vitro, IL-4, but not IL-13, induced a
significant decrease in barrier function, mucociliary clearance efficiency, and WRR on HNEC. In vitro,
dupilumab had no direct effect on HNEC and restored all epithelial functions primarily impaired by IL-
4 exposure. In vivo, after IND, both rFIX and rFIX-Fc were equally delivered to the blood compartment,
irrespective of the mouse strain studied, through a passive mechanism of transportation across the
mucosal barrier, independent of FcRn receptor. FIX activity levels were increased following IND in
FIX KO mice.
Conclusion: The PSI model should allow us to better characterize the severity of CRSwNP to target
patients eligible for biologics. Then, we have shown that in vitro, OSM, dysregulates the epithelial
barrier function through excessive epithelial WRR and the loss of ciliary function, leading to a chronic
inflammatory state that can evolve towards fibrosis. Thus, becoming a new potential therapeutic target.
Next, dupilumab was able, in vitro, to restore all tested epithelial functions (barrier, ciliary and wound
repair) and altered by IL-4 exposure, improving our understanding of its efficacy in vivo. Finally, we
have demonstrated that FIX passes through the bloodstream and its efficacy is preserved in mice, making
it possible to develop this route of administration in humans for the treatment of HB and probably other
biotherapies such as dupilumab.
Mots clés
Administration nasale
Anticorps monoclonal
Biothérapies
Biomarqueurs
Clairance mucociliaire
Culture primaire
Cellules épithéliales
Dupilumab
Epithélium nasal
Facteur IX
Hémophilie B
In vitro
Jonctions serrées
Polypose nasosinusienne
Chronic rhinosinusitis with nasal polyps
Résistance électrique transépithéliale
Voie d'administration
Domaines
Médecine humaine et pathologie
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Manuscrit PhD_Fieux M.pdf (11.64 Mo)
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Manuscrit PhD_Fieux M (1).pdf (11.64 Mo)
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