Abstract

Choroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), particularly when refractory to intraocular anti-VEGF injections. Here we report that treatment with the oral mineralocorticoid receptor (MR) antagonist spironolactone reduces signs of CNV in patients refractory to anti-VEGF treatment. In animal models of wet AMD, pharmacological inhibition of the MR pathway or endothelial-specific deletion of MR inhibits CNV through VEGF-independent mechanisms, in part through upregulation of the extracellular matrix protein decorin. Intravitreal injections of spironolactone-loaded microspheres and systemic delivery lead to similar reductions in CNV. Together, our work suggests MR inhibition as a novel therapeutic option for wet AMD patients unresponsive to anti-VEGF drugs.

Current treatments for age-related neovascular macular degeneration (nAMD) suffer from limited efficacy. Here, Zhao et al. show that pharmacological inhibition or genetic deletion of the mineralocorticoid receptor (MR) limits choroidal neovascularisation in rodents, and show in a pilot clinical study that targeting the MR pathway may provide clinical benefits in nAMD patiens.

Details

Title
Mineralocorticoid receptor antagonism limits experimental choroidal neovascularization and structural changes associated with neovascular age-related macular degeneration
Author
Zhao, Min 1 ; Mantel Irmela 2   VIAFID ORCID Logo  ; Gelize Emmanuelle 1 ; Li, Xinxin 1 ; Xie Xiaoyue 1 ; Arboleda, Alejandro 3 ; Seminel Marie 1 ; Levy-Boukris Rinath 1 ; Dernigoghossian Marilyn 1 ; Prunotto Andrea 4 ; Andrieu-Soler, Charlotte 5 ; Rivolta Carlo 6   VIAFID ORCID Logo  ; Canonica Jérémie 2 ; Naud Marie-Christine 1 ; Lechner, Sebastian 7 ; Farman Nicolette 7 ; Bravo-Osuna, Irene 8 ; Herrero-Vanrell Rocio 8 ; Jaisser Frederic 7 ; Behar-Cohen, Francine 9 

1  Inserm UMR_S 1138, Team 17, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) 
2  University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, Department of Ophthalmology, Lausanne, Switzerland (GRID:grid.9851.5) (ISNI:0000 0001 2165 4204) 
3  Inserm UMR_S 1138, Team 17, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; University of Miami Miller School of Medicine, Ophthalmic Biophysics Center, Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, USA (GRID:grid.26790.3a) (ISNI:0000 0004 1936 8606) 
4  University of Lausanne, Department of Computational Biology, Unit of Medical Genetics, Lausanne, Switzerland (GRID:grid.9851.5) (ISNI:0000 0001 2165 4204) 
5  IGMM, CNRS, Univ. Montpellier, Montpellier Cedex 5, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282) 
6  University of Lausanne, Department of Computational Biology, Unit of Medical Genetics, Lausanne, Switzerland (GRID:grid.9851.5) (ISNI:0000 0001 2165 4204) ; University of Leicester, Department of Genetics and Genome Biology, Leicester, UK (GRID:grid.9918.9) (ISNI:0000 0004 1936 8411) 
7  Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Inserm UMR_S 1138, Team 1, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) 
8  Universidad Complutense de Madrid, Department of Pharmacy and Pharmaceutical Technology, Madrid, Spain (GRID:grid.4795.f) (ISNI:0000 0001 2157 7667) ; Instituto Universitario de Farmacia Industrial, Faculty of Pharmacy, Universidad Complutense de Madrid, Madrid, Spain (GRID:grid.4795.f) (ISNI:0000 0001 2157 7667) ; Fundación para la Investigación-HCSC, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain (GRID:grid.4795.f) 
9  Inserm UMR_S 1138, Team 17, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Sorbonne University, University of Pierre et Marie Curie, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Paris Descartes University, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France (GRID:grid.417925.c) ; Assistance Publique - Hôpitaux de Paris, Hôtel-Dieu de Paris, Paris, France (GRID:grid.417925.c) 
Publication year
2019
Publication date
Jan 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-08125-6
ProQuest document ID
1886642847
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.