Targeted Removal of Disease-Causing Protein in Age-Related Macular Degeneration

We aim to fully characterize molecules that target pathogenic VEGF for degradation via the cell’s own waste disposal pathways.

We are developing a new treatment for neovascular Age-related Macular Degeneration (nAMD). nAMD is caused in part by accumulation of a protein called VEGF in a region of the eye where its levels are normally low. Currently, nAMD is treated by frequent eye injections of inhibitors which block VEGF function. We are using a new strategy, targeted protein degradation, to physically destroy VEGF using the body’s natural waste disposal system. Our ultimate goal is to create a more effective, localized, and longer-lasting therapy for nAMD that could improve patient outcomes and quality of life.

VEGF inhibitors are life-changing for many patients, but they act indiscriminately (inhibiting VEGF throughout the eye rather than just in the compartment where it is most pathogenic) and they also require relatively high concentrations to remain effective. We have developed a VEGF “degrader” that recruits VEGF to a lysosomal trafficking receptor with apical-specific RPE expression. This means our degrader has restricted activity to the apical RPE surface and can preserve VEGF in other ocular compartments (like the choroid) where it is required to sustain overall retinal health.

Upon completion of our study, we will have fully characterized the first protein-based degrader molecule for an ocular disease (to our knowledge). Our findings have the potential to (1) accelerate development of a treatment for individuals with neovascular Age-related Macular Degeneration that may be more long-lasting (reducing injection frequency) and more spatially targeted (reducing the rate of macular atrophy), and (2) show how this therapeutic modality can function in the eye, encouraging the development of degraders against future ocular targets.