Meteorin Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration

Abstract

The aim of this study was to evaluate the potential anti-angiogenic effect of MTRN (meteorin) in the laser-induced CNV rat model and explore its mechanisms of action. MTRN, thrompospondin-1, glial cell markers (GFAP, vimentin), and phalloidin were immuno-stained in non-human primate flat-mounted retinas and human retina cross sections. The effect of MTRN at different doses and time points was evaluated on laser-induced CNV at 14 days using in vivo fluorescein angiography and ex vivo quantification of CNV. A pan transcriptomic analysis of the retina and the RPE/choroid complex was used to explore MTRN effects mechanisms. In human retina, MTRN is enriched in the macula, expressed in and secreted by glial cells, and located in photoreceptor cells, including in nuclear bodies. Intravitreal MTRN administered preventively reduced CNV angiographic scores and CNV size in a dose-dependent manner. The highest dose, administered at day 7, also reduced CNV. MTRN, which is regulated by mineralocorticoid receptor modulators in the rat retina, regulates pathways associated with angiogenesis, oxidative stress, and neuroprotection. MTRN is a potential novel therapeutic candidate protein for wet AMD.

Mineralocorticoid pathway in retinal health and diseases

“…Although the anti‐angiogenic effect was mediated by a decrease in vascular endothelial growth factor ( VEGF) in retinal neovascularization model (Wilkinson‐Berka et al, 2019), it was independent from VEGF and VEGF family members in choroidal neovascularization. This was related, at least in part, to the up‐regulation of decorin (Zhao et al, 2019) and meteorin (Delaunay et al, 2021), that exert anti‐angiogenic effects on choroidal neovascularization. It was also demonstrated that upon mineralocorticoid receptor activation by aldosterone, microglial cells exhibited not only a pro‐inflammatory but also a pro‐angiogenic phenotype (Rana et al, 2020; Wilkinson‐Berka et al, 2019) and that spironolactone reduced the number and the activation state of retinal microglia in rodent models of retinopathy of prematurity (Deliyanti et al, 2012; Wilkinson‐Berka et al, 2009), of choroidal neovascularization (Zhao et al, 2019) and of diabetic retinopathy (Zhao et al, 2021).…”

Age-Related Macular Degeneration: New Insights in Diagnosis, Treatment, and Prevention

“…However, the increased, although still rare, the occurrence of intraocular inflammatory adverse events (which can lead to vascular occlusion and vision loss) for this new molecule means a change in the treatment paradigm toward injections that are more spaced out is likely, helped by its improved efficacy [21]. In the coming years, the therapeutic arsenal will be totally transformed by numerous molecules in development [22], and the discovery of new therapeutic targets [23], with the aim of reducing the therapeutic burden and improving visual outcomes.…”