Restoration of Crucial Retinal Lipids to Prevent Vision Loss in Age-Related Macular Degeneration

The goal of this project is to determine how specialized retinal lipids that are made within the eye and cannot be obtained from diet support and preserve vision as we age by evaluating whether restoring these lipids can reduce the cellular stresses driving vision loss in macular degeneration.

The proposal investigates whether very long-chain polyunsaturated fatty acids (VLC-PUFAs) are an essential fuel for the eye’s maintenance cells, RPE, which fail in AMD, leading to vision loss. Current drugs treat only the late stages of the disease. We hypothesize that VLC-PUFA loss is the cause of this critical failure. We will demonstrate this by using human RPE cells to map the metabolic pathway and, using gene therapy, rescue the disease in mice. Success validates VLC-PUFA restoration as a new preventative treatment for early AMD.

While current AMD therapies target late-stage inflammation, our approach addresses the early-stage metabolic disruptions that lead to irreversible damage. VLC-PUFAs are only synthesized locally within the retina by the ELOVL4 enzyme. This is the first study to systematically map how VLC-PUFAs are metabolized by retinal cells and to test whether restoring them can rescue retinal function and attenuate disease progression.

We will identify early biomarkers of AMD-related metabolic dysfunction, enabling intervention before irreversible vision loss. We will uncover why dietary omega-3 supplementation is insufficient and validate local VLC-PUFA restoration as a targeted strategy; our findings could lead to treatment paradigms that prevent AMD progression. This fulfills a critical unmet need since current FDA-approved treatments only manage late-stage disease, and no interventions yet target the early metabolic roots of AMD.