Local dysregulation of the alternative complement pathway in retinal pigment epithelium as a model for age-related macular degeneration

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Age related macular degeneration (AMD) is the most common cause of vision loss in the elderly of industrialized countries. The first signs and clinical hallmarks of early AMD are “drusen” which are extracellular deposits between Bruch’s membrane and the retinal pigment epithelium (RPE). The aetiology of AMD is not entirely understood and so far there is no evidence based treatment for early AMD. In this respect, elucidation of pathophysiological mechanism and possible new therapeutic targets is very important. Recent studies suggest that inflammatory immunological processes, particularly the complement system, are crucial for the development of AMD. Studies on the composition of drusen have revealed that they contain proteins of the alternative complement pathway. Furthermore genetic studies have shown a significant association between AMD and variants of complement system genes. The exact interaction of high risk genes and AMD pathophysiology is still unresolved. However, it can be assumed that the interplay from systemic and local changes of the innate immune system leads to local disease manifestation in the eye. The aim of this project is to analyse these links by investigating the consequences of dysregulation of the main components of the alternative complement pathway in the RPE of mice. Following subretinal injection of lentiviral vectors encoding complement and complement regulatory factors we shall examine the resulting phenotype and thus determine whether complement associated changes result in an AMD-like phenotype.