Final Report Summary - MICROGLIA AND AMD (Subretinal Microglia accumulation play a decisive role in the development of Age-related Macular Degeneration)
Age related macular degeneration (AMD) afflicts a growing number of subjects in Europe. It is the main cause of irreversible central vision loss. AMD is characterized by sizeable deposits of lipoproteinaceous debris called soft drusen (early AMD), choroidal neovascularisation (wet AMD), or by an extending lesion of the retinal pigment epithelium (RPE) and photoreceptors (geographic atrophy, GA). Choroidal neovascularisation, observed in “Wet” AMD are currently treated with intra-ocular injections of anti-vascular growth factor antibodies, which efficiently inhibit vessel formation and vessel leakage. However, this treatment does not improve the degenerative aspects of the “wet”-AMD patients and no efficient therapy exists for GA patients. Our research shows that inflammatory macrophages accumulate in the photoreceptor cell layer of AMD patients and that major genetic variations associated with AMD promote the subretinal inflammation. In AMD models, we show that this chronic subretinal inflammation promotes neovascularization and photoreceptor degeneration. We have deciphered distinct molecular mechanisms that lead to the recruitment and accumulation of these inflammatory cells and identified some of their pathogenic mediators. We showed that the pharmacological inhibition of these newly identified molecular pathways can treat subretinal chronic inflammation and associated pathologic neovascularization and photoreceptor degeneration in preclinical models of AMD. We have developed a pharmacological tool to inhibit the recruitment of inflammatory macrophages and continue to develop inhibitors of the discovered molecular pathways to prevent macrophage accumulation and neurotoxicity. We believe that the pharmacological development of the identified targets will be able to inhibit pathological subretinal inflammation in AMD and provide a therapy for the inflammation-associated degeneration.