Laying the Groundwork for Potential Age-Related Macular Degeneration Therapies

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Age-related macular degeneration (AMD) is a major cause of blindness, especially in older adults. A key feature of early AMD is the formation of drusen, clumps of debris made of lipids and proteins that collect between two layers at the back of the eye — the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM).

These drusen are not just signs of the disease; they actively contribute to vision loss by damaging the retina above them. Scientists suspect that lipoproteins — fat-protein complexes like high density lipoprotein (HDL) — play a big role in forming drusen. However, it wasn’t clear why these lipoproteins get stuck in BrM in the first place.

This study, published today in Proceedings of the National Academy of Sciences (PNAS) and led by Christopher B. Toomey, M.D., Ph.D., an assistant professor at the Viterbi Family Department of Ophthalmology, Shiley Eye Institute, UC San Diego School of Medicine, suggests that heparan sulfate (HS) in BrM is a major player in early AMD by trapping lipoproteins and kickstarting drusen formation. Targeting this sticky interaction might be a way to prevent or even reverse early signs of AMD before vision loss occurs.

Findings of the study:

• AMD patients had significantly more HS in the macular area of BrM than those without AMD.
• Lipoprotein-like particles (like HDL) clustered in areas rich in HS — suggesting HS may physically trap these particles.
• When the researchers treated AMD tissue with heparin (a compound similar to HS), they were able to wash out these lipoproteins. This confirmed that the particles were indeed sticking to the HS.
• Lipoproteins showed strong binding to BrM, but only if the HS was intact. When HS was removed, or when they added special heparin-like molecules, the binding stopped. This suggests it may be possible to prevent or reverse lipoprotein buildup in BrM using therapeutic agents that interfere with this interaction.

The study also shows the promise of non-blood-thinning forms of heparin as potential treatments. These could help “wash away” harmful lipids without the bleeding risks of regular heparin.