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Samy Omri, Houda Tahiri, Katia Mellal, william lubell, huy ong, Sylvain Chemtob; CD36 receptor modulator as potential drug candidates for the treatment of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):775.
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© ARVO (1962-2015); The Authors (2016-present)
Pathophysiological inflammation of the age–related macular degeneration (AMD), is associated with sub retinal macrophage accumulation and activation. CD36 is an interesting target expressed in macrophages, involved in uptake of oxidized lipids, induction of inflammation and modulation of angiogenesis. The present study investigated shows the modulatory effect of novel CD36 ligands in reducing the inflammatory response but also Bruch’s membrane deposits and choroidal neovascularization.
Based on in vitro study, we selected 2 ligands (DBG178 and YGR212-4) showing anti-inflammatory effect.Their properties were tested in different in vivo models.Lipid homeostasis effect of the CD36 ligands was tested on apoE-/- mice treated with NaCl, DBG178 or YGR212-4 fed on high fat high cholesterol diet. Enucleated eyes were prepared for observation by transmission electron microscopy. Bruch’s membrane thickness was measured as an index of lipid homeostasis. The protective effect of CD36 ligands on inflammation and photoreceptors were performed on CX3CR1-/-mice submitted to photooxidative stress by blue light exposure (425 nm), treated with NaCl, DBG178 or YGR212-4. The number of macrophages/microglia in sub retinal space was quantified with immunofluorescence on retinal pigment epithelium flatmount preparations or cryosections. We also studied inflammatory markers with immunofluorescence and RT-PCR performed on cells in sub retinal space microdissected with laser. Outer nuclear layer thickness was measured as an index of photoreceptors integrity. The angiogenic effect of these CD36 ligands was tested with a model of neovascularization of choroidal explants and in an in vivo model of laser impact-induced CNV.
Treatments with CD36 ligands DBG178 and YGR212-4 decrease the Bruch’s membrane deposits and thickness by 20%. They also impact the anti-inflammatory response by decreasing activated macrophages accumulation in the sub retinal microenvironment by 60%. The integrity of photoreceptors layers was preserved with treatment. These CD36 ligands inhibited choroidal neovascularization in ex vivo choroid explant and in vivo on laser induced neovascularization model respectively by 65%.
Modulation of the CD36 activation by selective CD36 ligands appears to be a potential approach for the pharmacotherapy of dry and wet form AMD which remains an unmet medical need.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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