July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Pharmacological antagonism of mineralocorticoid receptor exerts VEGF-independent anti-angiogenic effects: Implication for wet AMD
Author Affiliations & Notes
  • Francine F Behar-Cohen
    Ophthalmology, Lausanne University, H�pital Cochin, Inserm UMR1138, Paris, France
  • Irmela Mantel
    Ophthalmology, Lausanne University, H�pital Cochin, Inserm UMR1138, Paris, France
  • Emmanuelle Gelize
    Ophthalmology, Lausanne University, H�pital Cochin, Inserm UMR1138, Paris, France
  • Carlo Rivolta
    Ophthalmology, Lausanne University, H�pital Cochin, Inserm UMR1138, Paris, France
  • Jérémie Ganonica
    Ophthalmology, Lausanne University, H�pital Cochin, Inserm UMR1138, Paris, France
  • Frederic Jaisser
    Ophthalmology, Lausanne University, H�pital Cochin, Inserm UMR1138, Paris, France
  • Min Zhao
    Ophthalmology, Lausanne University, H�pital Cochin, Inserm UMR1138, Paris, France
  • Footnotes
    Commercial Relationships   Francine Behar-Cohen, INSERM (P); Irmela Mantel, None; Emmanuelle Gelize, None; Carlo Rivolta, None; Jérémie Ganonica, None; Frederic Jaisser, None; Min Zhao, INSERM (P)
  • Footnotes
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Investigative Ophthalmology & Visual Science July 2019, Vol.60, 975. doi:https://doi.org/
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      Francine F Behar-Cohen, Irmela Mantel, Emmanuelle Gelize, Carlo Rivolta, Jérémie Ganonica, Frederic Jaisser, Min Zhao; Pharmacological antagonism of mineralocorticoid receptor exerts VEGF-independent anti-angiogenic effects: Implication for wet AMD. Invest. Ophthalmol. Vis. Sci. 2019;60(9):975. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Choroidal neovascularization (CNV) is a major cause of visual impairment in wet age-related macular degeneration (nAMD) patients. Anti-VEGF is currently the only treatment but about 40% of macula remain “wet” despite optimal treatment. Although AMD is recognized as low-grade inflammatory disease, glucocorticoids are not efficient in reducing CNV or its associated macular edema. Hypothesizing that mineralocorticoid receptor (MR) pathway contributes to the disease mechanism, we evaluated MR antagonists in rat experimental CNV. Spironolactone was evaluated add on anti-VEGF in nAMD patient refractory to anti-VEGF.

Methods : Laser-induced CNV was performed in rats treated with systemic spironolactone (25 mg/kg/day) or ith wthe more MR-specific eplerenone (200 mg/kg/day) for 14 days. Intravitreous rat anti-VEGF was used as positive control. Anti-angiogenic effect of decorin, aldosterone-targeted gene, was tested using siRNA injected in rat eyes. A prospective clinical pilot study included 20 nAMD patients with refractory intra- or subretinal fluid despite intensive anti-VEGF regimen. In addition to monthly injections of anti-VEGF during 6 months study period, they received adjuvant oral spironolactone (25mg week 1, 50mg until Month 3, 25mg until Month 4, 0mg until Month 6). SD-OCT was performed using follow-up mode. Clinical Trials.gov Identifier: NCT03744767

Results : Bothl MR antagonists reduced CNV volume and leakage as efficiently as anti-VEGF in rats. Spironolactone and anti-VEGF had additive effects on CNV leakage. Spiro did not reduce VEGF but reduced MCP1 and increased the expression of decorin. Intravitreal siRNA against decorin abrogated partially the anti-angiogenic effect of spiro.
In eyes from patients with refractory nAMD, statistically significant changes were observed maximal at Month 3 compared to baseline in central retinal thickness (p = 0.011) and volume (p = 0.012), in the foveal thickness (p = 0.039), the thickest cystic changes (p = 0.040), and subretinal fluid (p = 0.014). The improvements were lost after stopping spironolactone at Month 4 although anti-VEGF injections alone were continued

Conclusions : MR antagonism prevents CNV through a VEGF-independent mechanism, is additive with anti-VEGF and mediated by up-regulation of decorin. These preclinical and clinical results identify the MR as a novel molecular regulatory target for nAMD.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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