Investigations of the inflammatory pathogenesis of age related macular degeneration and a therapeutic role for Minocycline

Age related macular degeneration (AMD) is the leading cause of blindness in people over the age of 50 in the western world. The wet form of AMD is associated with choroidal neovascularisation. The pathogenesis of choroidal neovascularisation is complex involving neovascular growth, vascular leakage, hypoxia and inflammation. Evidence suggests that immunological events play a key role in the pathogenesis of AMD. In AMD a chronic low grade inflammatory process may instigate the pathophysiological process culminating in eventual visual loss. Minocycline is a tetracycline derivative with anti-inflammatory in addition to antibiotic effects. This study investigated the effects of minocycline on retinal pigment epithelial cells in culture. Cell viability and apoptosis was studied with flow cytometry. Cells were exposed to glycated albumin and hypoxia as these processes occur during ageing. The effects of minocycline on IL-8 and MCP-1 production from ARPE-19 cells in culture were investigated with enzyme linked immunosorbent assay. The results showed a potential narrow therapeutic window for minocycline to act on retinal pigment epithelial cells. Cell viability decreased rapidly at minocycline doses above 5μM. Minocycline suppressed the production of inflammatory cytokines IL-8 and MCP-1 in cell culture. A clinical trial was conducted to investigate whether combination therapy aimed at targeting different pathways in the AMD disease process would be effective. This trial was powered to determine adverse events when a quadruple therapy ii of reduced fluence photodynamic therapy (PDT), intravitreal ranibizumab, dexamethasone and oral minocycline were used as treatments. The clinical trial demonstrated that anti-VEGF treatment administered in combination with other agents was not as effective as monthly anti-VEGF monotherapy at sustaining visual improvement. However, the trial did demonstrate that combination therapy could be delivered safely. The results demonstrate that minocycline has a potential therapeutic role for the inflammatory changes in neovascular age related macular degeneration.