Methods and compositions for reparing airway epithelial cell in fibrosis cystic patient

The present invention relates to the treatment of fibrosis cystic. The inventors have demonstrated that specialised pro-resolution lipid mediators (SPMs) regulate tight junction formation and prevent its disruption during Aspergillus fumigatus infection of CF airway epithelial cells. Moreover, they have demonstrated that these SPMs repair the CF airway epithelial cells. Thus, the invention relates to methods and pharmaceutical compositions for the treatment of cystic fibrosis. The present invention also relates to methods and pharmaceutical compositions for treating or preventing Aspergillus fumigatus infection in patient suffering from cystic fibrosis.

In cystic fibrosis (CF), impaired mucociliary clearance leads to chronic infection and inflammation. However, cilia beating features in a CF altered environment, consisting of dehydrated airway surface liquid layer and abnormal mucus, have not been fully characterized. Furthermore, acute inflammation is normally followed by an active resolution phase requiring specialized proresolving lipid mediators (SPMs) and allowing return to homeostasis. However, altered SPMs biosynthesis has been reported in CF. Here, we explored cilia beating dynamics in CF airways primary cultures and its response to the SPMs, resolvin E1 (RvE1) and lipoxin B4 (LXB4). Human nasal epithelial cells (hNECs) from CF and non-CF donors were grown at air-liquid interface. The ciliary beat frequency, synchronization, orientation, and density were analyzed from high-speed video microscopy using a multiscale Differential Dynamic Microscopy algorithm and an in-house developed method. Mucins and ASL layer height were studied by qRT-PCR and confocal microscopy. Principal component analysis showed that CF and non-CF hNEC had distinct cilia beating phenotypes, which was mostly explained by differences in cilia beat organization rather than frequency. Exposure to RvE1 (10 nM) and to LXB4 (10 nM) restored a non-CF-like cilia beating phenotype. Furthermore, RvE1 increased the airway surface liquid (ASL) layer height and reduced the mucin MUC5AC thickness. The calcium-activated chloride channel, TMEM16A, was involved in the RvE1 effect on cilia beating, hydration, and mucus. Altogether, our results provide evidence for defective cilia beating in CF airway epithelium and a role of RvE1 and LXB4 to restore the main epithelial functions involved in the mucociliary clearance.

Keywords: Cystic fibrosis, SPMs, RvE1, LXB4, Aspergillus fumigatus
Patent Application number: European Procedure (Patents) (EPA) - 07 Juin 2022 - 22 305 824.9
Inventors:
URBACH ValerieSY Khadeeja AdamBOTTEREL Françoise
Publications:
Briottet Maëlle et al. /u201cSpecialized proresolving mediator resolvin E1 corrects the altered cystic fibrosis nasal epithelium cilia beating dynamics./u201d Proceedings of the National Academy of Sciences of the United States of America vol. 1215 (2024): e2313089121.

Reference:

BIO22248-T1

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