CE17 - Recherche translationnelle en santé

Towards clinical investigation on the use of Mineralocorticoid Receptor Antagonist for wet Age-Related Macular Degeneration – MR-A-MD

Towards clinical investigation on the use of Mineralocorticoid Receptor Antagonist for wet Age-Related Macular Degeneration

Wet AMD remains a major cause of vision loss despite anti-VEGF therapy due to frequent re-injections, geographic atrophy, fibrosis and no effects on neovessel growth. Based on pre clinical results and pilote clinical study, we propose an alternative therapy using antagonism of mineralocorticoid receptors (MRA).<br />MR-A-MD aims at developing a local formulation of spironolactone and identifying molecular and imaging markers to optimize the design of a prospective randomized clinical trial.

preparing a trial testing mineralocorticoid receptor antagonists for wet AMD

Strategies that aim at extending the duration of anti-VEGF effects (gene therapy, small antibodies, implantable reservoir) will not benefit to all patients because VEGF is not the only molecular target in AMD31. MR-A-AMD aims at validating that MR pathway is a novel and pertinent target to be tested in patients with wet AMD poorly responsive to anti-VEGF therapy30. In addition, we will search for imaging and biological markers of MR-pathway activation in wet AMD patients to select the best responders to MRA and thus reduce the number of patients required in a clinical trial.<br />We propose a combination of original experimental approaches to evaluate the effect of MRA (alone or combined with anti-VEGFs) on the pathogenic consequences of CNV in humans. These experiments will help understand the mechanisms of action of MRA and identify subsequent pertinent clinical endpoints.

-Study mechanisms involved in fluid accumulation in/ or under the retina (macular edema) using human RPE cells and in vivo ICG angiography and transport analysis.
- Study the role of MR on choroidal neuromuscular regulation using human retina and transgenic rats over expressing MR and functional testing in vivo in humans.
- Study effect of MRA and dowstream regulated targets on sub retinal fibrosis and RPE epithelia to mesenchymal transition
- Analyze molecular biomarkers in the serum and ocular fluids of patients with AMD treated with anti-VEGF and imaging biomarkers
- develop and test an intraoculaire spironolactone formulation

- Spironolactone suspension allowing for at least 3 months release was developed and is safe in rats in vivo.
- Demonstration that mid-phase ICG hyperfluorescent plaques correspond to RPE dysfunction and that MR hyperactovation enhances RPE uptake of ICG ex vivo and in vivo. Analysis of late phase hyperfluoresecnt plaque as a response to anti-VEGF treatment.
- Identification of the neural choroidal system in rats and humans and demonstration that MR activation alters the choroidal neuromuscular network.
- Validation of in vivo RPE imaging analysis as a tool to monitor RPE cells in humans
- Measurement of corticoids in ocular media using mass spectrometry and demonstration of a local corticoid ocular homeostasis.
- Demonstration that Spiro and decorin exert anti fibrotic effects
- collection of ocular media and blood from control and patients treated with anti-VEGF

We have identified that choroidal neuromuscular abnormalities are biomarkers of MR pathway activation.
We need to correlate animal data to human images. This could be an important biomarker to select patients.
We have shown that ocular corticoids can be measured in the eye and are regulated independently from systemic corticoids. Levels in AMD and response to treatment must be performed.
We have shown that decorin is unregulated by spironolactone and prevent fibrosis and EMT of RPE and we have identified the mechanisms involved in these effects.
We have produced a local formulation of intraoculaire treatment and we need to perform the PK studies in rabbits.
We have shown that ICG can be used to monitor RPE transport capacities and need now to correlate Late ICG to response to treatment and to MR pathway activation.

Mid-Phase Hyperfluorescent Plaques Seen on Indocyanine Green Angiography in Patients with Central Serous Chorioretinopathy.
Bousquet E, Provost J, Zola M, Spaide RF, Mehanna C, Behar-Cohen F.
J Clin Med. 2021 Sep 30;10(19):4525.

in vivo Retinal Pigment Epithelium Imaging using Transscleral OPtical Imaging in healthy eyes
Laura Kowalczuk Rémy Dornier, Mathieu Kunzi, Antonio Iskandar, Zuzana Misutkova, Aurélia Gryczka, Aurélie Navarro, Fanny Jeunet, Irmela Mantel, Francine Behar-Cohen,Timothé Laforest,Christophe Moser Ophthalmology Science -Accepted for publication

Submission of «Indocyanine green angiography of type 1 macular neovascularization in age-related macular degeneration and central serous chorioretinopathy reveals different disease mechanisms.« (the «Work«), by Marta Zola, to RETINA The Journal of Retinal and Vitreous Diseases

Chronic Systemic Dexamethasone Regulates the Mineralocorticoid/Glucocorticoid Pathways Balance in Rat Ocular Tissues.Zola M, Mejlachowicz D, Gregorio R, Naud MC, Jaisser F, Zhao M, Behar-Cohen F.
Int J Mol Sci. 2022 Jan 24;23(3):1278.

Age-related Macular Degeneration (AMD) is the leading cause of blindness after age 60 in industrialized countries. AMD is a multifactorial disease that comes in two forms: a "dry" form and a "wet" or neovascular form. The neovascular form complicates about half of AMD and involves the growth of abnormal vessels (CNV) from the choroid, which are responsible for a rapid and severe decline in vision. The mechanisms of visual decline are multiple: - formation of an edema by collection of sub or intra-retinal fluid, - damage then destruction of the cells of the pigmentary epithelium of the retina, - fibrosis, - hemorrhage.
Intravitreal injection of anti-VEGF reduces very effectively the macular edema associated with CNV and is fully effective in the long term, at the cost of repeated injections, in 40% of wet AMD. Although having revolutionized the management of AMD, anti-VEGFs are not effective in all patients and act only on the permeability of CNV and not on all the mechanisms responsible for visual impairment.
Using pharmacological and transgenic approaches, we showed that blocking the mineralocorticoid (MR) pathway was effective in relevant models of wet AMD. In a small cohort of patients with very advanced wet AMD, an oral MR pathway antagonist (MRA) potentiated the effects of anti-VEGF. A patent has been issued to protect the use of MRAs in the treatment of anti-VEGF-resistant wet AMD. In order to optimize the design of a prospective clinical trial designed to test MRA in anti-VEGF-responsive wet AMD, we propose to - search for molecular and imaging biomarkers, derived from preclinical experiments, to screen patients more likely to respond to MRAs, - identify the best route and timing for MRA administration, - develop a local formulation of clinical grade MRAs. These different elements will reduce the risk of translational failure between pre-clinical studies and a randomized controlled trial and reduce the number of patients required in a clinical trial. The repositioning of a long-established drug into a medical grade ophthalmologic formulation will allow for rapid transfer to the clinic for the benefit of patients. An important asset of this project, carried out in collaboration with Fareva, which is well known in drug manufacturing and is equipped to produce small pharmaceutical batches suitable for trials, is that it will allow the production of a new formulation of a well-known drug in a medical grade ophthalmological formulation, which will be rapidly transferred to the clinic for the benefit of patients

Project coordination


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.


CRC Centre de recherche des Cordeliers

Help of the ANR 732,180 euros
Beginning and duration of the scientific project: December 2020 - 42 Months

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