Whether concerning the cornea or the retina, the loss of transparency leads to an alteration in vision. Corneal opacities can result from developmental disorders or inadequate repair processes, while macular oedema and fibroglial and vascular remodelling affect transparency and retinal function. By targeting complementary pathways, we develop targeted therapies aimed at restoring tissue integrity and optical quality.
Restoration of corneal transparency through the local modulation of PAX6 in aniridia-induced corneal opacity (Daniel Aberdam, Dominique Bremmong-Gignac)
Aniridia is a rare autosomal dominant panocular blinding disorder which occurs in carriers of mutations in the PAX6 gene, encoding for an evolutionary conserved transcription factor essential for eye development. This haplo-insufficiency for PAX6 results in malformation of most eye structures including aniridia and associated keratopathy (AAK), a progressive degeneration of the corneal stem cell niche and function reducing transparency of the cornea. The best treatments today result in only temporary improvement of vision before blindness occurs.
The objective of the research is to develop a novel therapeutic strategy using selected small compounds able to rescue PAX6 haploinsufficiency. The mechanism of action (MOA) of the repurposing four drugs will be studied on both human limbal stem cells and mouse models of inflammation and neovascularization. Solubility, formulation for topical application, and in vivo toxicity will be challenged for each compound. Cohorts of patients with aniridia are phenotyped in Necker Hospital. This work has received support from European grants.
Modulating mineralo-glucocorticoid pathways in corneal wound healing (Daniela Braz, F. Behar-Cohen, JL Bourges, Min Zhao)
Attacked by infectious or chemical agents, metabolic, traumatic or surgical braids, the cornea is the site of an inflammatory reaction which must be controlled to limit tissue damage. The modulation of corticoid receptors enables the anti-inflammatory effects of glucocorticoids to be optimised by limiting their side effects and the delays in healing which they induce.
The project aims to develop formulations of small molecule eye drops that antagonise the mineralocorticoid receptor and to identify the molecular targets that beg for their anti-angiogenic, anti-oedematous and anti-fibrotic effects with the aim of discovering new therapeutic molecules. Patients are phenotyped in Cochin hospital for future therapeutic studies.
Targeting mineralocorticoid pathway to treat macular edema (Min Zhao, Dan Mejlachowicz, Elodie Bousquet, F Behar-Cohen)
Using pharmacological and transgenic approaches, we showed that blocking the mineralocorticoid (MR) pathway was effective to reduce CNV growth and leakage in animals, to reduce edema in models of central serous chorioretinopathy and of diabetic retiniopathy.
In order to optimize the design of a prospective clinical trial to test MRA in anti-VEGF-responsive wet AMD, in diabetic retinopathy and central serous chorioretinopathy, we propose to conduct preclinical and clinical research to better understand on which mechanisms induced in vision loss in the time course of diseases MRA are effective, and to identify biomarkers of these mechanisms to better select patients amenable to MRA. The repositioning of a long-established drug into a medical grade ophthalmologic formulation, prepared by an industrial partner, will allow for rapid transfer to the clinic for the benefit of patients. Patients are phenotyped clinically and molecularly in Cochin hospital.
This work has received support from ANR and AVISAN-UNADEV.
Targeting the retinal pigment epithelium to reduce vision loss in high myopia (Kim Delaunay, A. Torriglia, Behar-Cohen)
The incidence of myopia is increasing worldwide. Vision loss results from abnormal elongation of posterior segment leading to staphyloma and maculopathy.
Our project is to study the influence of light and corticoid hormones on the regulation of genes expressed in the retinal pigment epithelium, known to intervene in myopia and involved in the remodeling of choroid and retina. Ultimately, we will identify new molecular targets to regulate specifically the pathologic and blinding consequence of high myopia. This work has received financial support from Fondation de France.