Genetic and molecular biomarkers for geographic atrophy

Abstract

Geographic atrophy (GA) is characterized by atrophy of the retina, retinal pigment epithelium and choriocapillaris, causing a gradual loss of vision over time. Treatment options to prevent initiation or progression of GA are limited; two recently FDA-approved inhibitors of the complement system (pegcetacoplan, avacincaptad pegol) showed a modest decrease in GA lesion growth in phase 3 clinical trials. Exploration of genetic and molecular biomarkers in GA plays a critical role in our battle against this blinding disease to improve early disease detection, to find more effective therapies, and to provide personalized care to patients. In this review, we provide a comprehensive overview of the current literature investigating genetic and molecular biomarkers for GA. Genetic studies identified multiple genes and variants that play a role in progression to GA and GA lesion growth, involving pathways such as complement activation, extracellular matrix interaction and lipid metabolism. The number of published studies assessing molecular biomarkers for GA initiation and progression in ocular matrices is limited. Several studies evaluated molecular biomarkers in the systemic circulation, showing higher levels of complement activation and a causal role of lipid subfractions in GA. Larger, well-powered studies are needed to identify novel and validate existing biomarkers, and to investigate the potential of combining genetic and molecular markers with imaging techniques for more accurate diagnosis and monitoring of GA. The development of personalized medicine approaches based on individual genetic and molecular profiles could hold promise for more effective and targeted treatments for this devastating disease.

Keywords: GA; genetics; geographic atrophy; lesion growth; molecular biomarkers; progression.