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.
Highlights
Choroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), when refractory to intraocular anti-vascular endothelial growth factor (VEGF) injections
Twenty patients with neovascular AMD (nAMD) presenting with refractory intra- or subretinal fluid despite monthly intravitreal injections of antiVEGF (≥12 months anti-VEGF treatment, ≥6 months refractoriness despite monthly injections, using the same anti-VEGF molecule (Aflibercept in 13 eyes/Ranibizumab in 8 eyes), ≥350 μm on thickest A-scan on optical coherence tomography (OCT)) consented to participate to a prospective pilot study
In 21 eyes of 20 patients with refractory nAMD (13 females, mean age 76.3 ± 7.7 (SD) years received 37.2 ± 17.1 anti-VEGF injections given over a mean period of 46.0 ± 19.8 (SD) months prior to study enrollment), statistically significant changes in structural outcome measures, maximal at Month 3 compared to baseline, were observed on spectral domain OCT (SD-OCT) at various time points during spironolactone treatment (Fig. 1)
Summary
Choroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), when refractory to intraocular anti-VEGF injections. We report that treatment with the oral mineralocorticoid receptor (MR) antagonist spironolactone reduces signs of CNV in patients refractory to anti-VEGF treatment. Heredity, diet, smoking, obesity, and vascular diseases are involved in the pathogenesis of AMD2; the exact mechanisms leading to CNV remain incompletely understood. CNV is not specific to AMD, it may complicate multiple other diseases affecting the retinal pigment epithelium (RPE) and the choroid, including high myopia and central serous chorioretinopathy (CSCR). In addition to vascular endothelial growth factor (VEGF) family members and their receptors[6], complement components and proinflammatory molecules accumulating in the RPE-choroid complex[7], such as cytokines and angiopoietins[8], contribute to CNV growth. Multiple molecular pathways have been implicated in the formation and maintenance of CNV, the treatment of nAMD currently relies on biologic compounds that only neutralize
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