A systems biology approach to decode early age-related macular degeneration and its progression to advanced disease

• Applicant: Dr. Julian Wolf
• Subject Area: Ophthalmology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562222475

Age-related macular degeneration (AMD) is the most common cause of visual impairment in developed countries and it is expected that about 300 million people will be affected by 2040. It is estimated that 8.7% of people between 45 and 85 years are affected by AMD, further demonstrating its substantial global burden. Current therapeutic approaches are only available for late-stage AMD with the goal to delay further progression. However, there are still no therapies available for patients with early AMD, who represent the largest fraction of AMD patients. This illustrates the significant unmet medical need to improve our molecular understanding of early AMD and its progression to late-stage AMD, with the ultimate goal to develop novel therapeutics for early AMD. Such early intervention may not only reduce suffering for patients with early AMD, but may also reduce the risk of disease progression to late-stage AMD. High-resolution molecular and cell level analyses are critical to understand disease mechanisms, but are impractical in non-regenerative organs like the eye because tissue biopsies would cause serious functional damage. We recently developed a systems biology tool that integrates high-resolution proteomics of liquid biopsies from the anterior chamber of the human eye, artificial intelligence, and single-cell transcriptomics of all known ocular cell types, allowing us to investigate molecular and cellular driver in the eye of living patients. In my group in Freiburg, we will 1.) apply high-resolution proteomic profiling of aqueous humor liquid biopsies to determine proteomic signatures and pathways affected in eyes with early AMD and how these patterns change during disease progression to neovascular AMD and geographic atrophy, 2.) apply our systems biology approach to estimate which cell types are particularly involved in each AMD stage, validate our findings using cell level transcriptomics and proteomics of human AMD tissue specimens, and apply our AI proteomics eye aging clocks to investigate the role of accelerated cellular aging in AMD stages, and 3.) develop aqueous humor proteomics-based AI-risk stratification tools to identify patients with early AMD at high risk for progression to late-stage AMD. The results of this project will improve our molecular and cellular understanding of early AMD and will provide new insights into the mechanisms associated with its progression to late-stage AMD. Our findings may ultimately inspire novel therapeutics for patients with early AMD, which may reduce the risk of progression to late-stage AMD. The support of the DFG will be fundamental to realize this vision.

• DFG Programme: Emmy Noether Independent Junior Research Groups