Role of Corticoids in Ocular Rosacea – ROCOR
Role of Corticoids in Ocular Rosacea
Ocular rosacea (OR) is a common but underdiagnosed ocular surface disease. It alters significantly the quality of vision and life and can threaten the visual prognosis as no treatment is available. OR results from chronic neurovascular and inflammatory mechanisms that can be triggered by corticosteroids. But the mechanisms linking corticoids and neurovascular, immune dysregulation and meibomian gland dysfunction (MGD) in OR are unknown.
Validate the original hypothesis that inadequate activation of the mineralocorticoid pathway by corticoids could link all pathogenic features of OR.
Due to the limited understanding of disease mechanisms and the lack of specific diagnostic tests, OR is underdiagnosed. Yet, it is estimated that 10 to 50% of patients with skin rosacea (representing 10% of the general adult population) have ocular involvement. The current therapeutic options offer only indirect and nonspecific approaches or address already existing damage, leaving patients in distress and with reduced quality of vision and life. There is therefore a crucial need for diagnosis and better treatment for OR.<br />Our hypothesis is based on more than 10 years of work on the role of mineralocorticoid pathway in ocular diseases and in the skin, which has shown that activation of the mineralocorticoid receptor (MR) regulates inflammation, immunity, vascular function and lipid metabolism, thus linking all symptoms of OR.<br />The objectives of this project are: 1) to decipher the role of endogenous corticosteroid dysregulations in the pathogenesis of OR, 2) to highlight the contribution of MR pathway activation in meibum secretion (lipid secretion from the Meibomian gland) and in MGD, 3) to identify biomarkers of corticoid pathway deregulation in the meibum of patients with OR in order to select patients amenable to MR blockade. MR antagonists existing as generic molecules could be repurposed and formulated for topical ocular use.
The use of animals and human biological samples in this project has been approved by ethical committee and authorized by the administration.
Using a new transgenic rat model overexpressing the human MR with experimental models of OR induced by endogenous and exogenous stimuli (glucocorticoids, UVB and cathelicidin LL37), we will elucidate the consequences of MR pathway activation: - on the pathogenic features associated with OR (work package 1, WP1), - on the MGD and on the lipid profile of meibum (WP2). Using a non-targeted lipidomic analysis (LC-HRMS), we will search for biomarkers of MR activation in human meibum in order to identify patients amenable to local MR blockade (WP3). A new medical grade topical formulation of the MR antagonist has been prepared and will be used not only for animal experiments, but also for further clinical trials.
- MR expression is increased in ocular tissues of patients with OR.
- Corneal neovascularization (a severe vision-threatening complication of OR) induced by limbal deficiency is alleviated by MR blockade. Combined treatment of MR antagonist and glucocorticoid exerts synergistic anti-inflammatory and anti-angiogenic effect and improves the corneal reepithelialization delayed by glucocorticoids.
- The P1hMR transgenic rat stably expresses hMR in ocular surface tissues including the cornea, conjunctiva and meibomian gland. The expression of rat GR and MR is not altered.
- Ocular injection of LL37 induces corneal edema and inflammatory cell infiltration in the conjunctiva, similar to OR.
This project will provide new insights into disease mechanisms by linking MR activation to all pathogenic features of OR. Identification of meibum lipid biomarkers of MR activation in patients with OR will allow for improved diagnosis and selection of patients for targeted treatment with MR antagonists. The medical grade formulation of the MR antagonist used in our project will facilitate subsequent clinal trials and drug development. In addition, the lipid biomarkers and the treatment with the MR antagonists could be patented.
-Rodrigues-Braz D, Zhao M, Yesilirmak N, Aractingi S, Behar-Cohen F, Bourges JL. Cutaneous and ocular rosacea: common and specific physiopathogenic mechanisms and study models. Mol Vis. 2021;27:323-353. eCollection 2021.Open Access
-Rodrigues-Braz D, Bonnet C, Zhao M, Behar-Cohen F. Anti-angiogenic, anti-inflammatory, and anti-edematous effects of mineralocorticoid receptor antagonism in a rat model of corneal neovascularization. The Association for Research in Vision and Ophthalmology, May 2021, San Francisco, California, USA. (Poster)
-Rodrigues-Braz D, Bonnet C, Zhao M, Behar-Cohen F. Therapeutic potential of combination treatment of mineralocorticoid receptor antagonist and glucocorticoids in a rat model of corneal neovascularization. The Association for Research in Vision and Ophthalmology, May 2022, Denver, Colorado, USA. (Poster)
Ocular rosacea (OR) is a common but underdiagnosed ocular surface disease. It alters significantly the quality of vision and life and can threaten the visual prognosis as no treatment is available. OR results from chronic neurovascular and neuro-inflammatory mechanisms that can be triggered by corticosteroids. But the mechanisms linking corticoids and neurovascular, immune dysregulation and meibomian gland dysfunction (MGD) in OR are unknown. Based on solid preliminary results, ROCOR aims at validating the original hypothesis that inadequate activation of the mineralocorticoid pathway (MR) by corticoids could link all pathogenic features of OR. Using a recently developped transgenic rat model overexpressing hMR with experimental models of OR induced by endogenous and exogenous stimuli (glucocorticoids, UVB and cathelicidin LL37), we will elucidate the consequence of MR pathway activation: - on pathogenic features associated with OR (WP1), - on MGD and on meibum lipid profile (WP2). Using a non-targeted lipidomic analysis (LC-HRMS), we will search for biomarkers of MR activation in human tears and meibum in order to identify patients amenable to local MR blockade (WP3).Our consortium combines complimentary expertise and methodologies to reach our objectives. This project will provide new knowledge on the mechanisms of the disease, propose specific lipid biomarkers of OR and open targeted therapeutic options for OR.
Project coordination
Min ZHAO (CENTRE DE RECHERCHE DES CORDELIERS)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
CRC CENTRE DE RECHERCHE DES CORDELIERS
CRC CENTRE DE RECHERCHE DES CORDELIERS
CSGA Centre des Sciences du Goût et de l’Alimentation
Help of the ANR 601,700 euros
Beginning and duration of the scientific project:
December 2021
- 42 Months
