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Curbing Drusen Buildup in Dry AMD
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. There are effective treatments for the ‘wet’ stage of the disease. But treatments targeting the more prevalent, slower progressing, and ultimately more threatening ‘dry’ form of the disease have so far had minimal impact.
Dry AMD is the primary research focus of Kellogg clinician-scientist Jason Miller, M.D., Ph.D. His lab aims to better describe and ultimately disrupt a primary pathway of the disease—lipid (fat) deposits called drusen that build up outside of the retinal pigment epithelium (RPE).
The RPE is a vital cell layer at the back of the eye that supports the photoreceptor cells (PRs) that convert light to sight. In dry AMD, drusen accumulation ultimately destroys the RPE. Left unprotected,PRs subsequently die, leading to vision loss.
“We know that lipids are one source of energy for the RPE,” Dr. Miller explains. “And there is good evidence that the toxic drusen buildup we see in dry AMD is largely a by-product of the RPE casting off lipids it doesn’t use, like trash piling up in an alley.”
In consultation with lipidomics expert Subramaniam Pennathur, M.D., Chief of Michigan Medicine’s Division of Nephrology, the Miller lab will conduct studies to understand how those piles build up and explore ways to reduce their size. Three new grants will fund this work:
The E. Matilda Ziegler Foundation for the Blind and Eversight Eye & Vision Research will support complementary projects to better describe the processes by which the RPE secretes lipids and deposits discarded lipids as drusen outside the RPE. A Foundation Fighting Blindness grant will explore strategies to minimize the amount of drusen buildup.
Dr. Miller’s lab also continues to receive instrumental support from the James Grosfeld Initiative for Dry AMD, whose funding led to the preliminary data necessary to successfully compete for these external grants. Additional support comes from the Discovering Hope Foundation.
The Miller lab previously confirmed what logic would suggest: that if the RPE consumes more fat, that will leave less to discard. “We will now focus on encouraging the RPE to maximize its consumption of available lipids,” says Dr. Miller, “We’ll also attempt to identify obstacles that might keep that from happening.”
“One project will attempt to persuade the RPE to make lipids its sole energy source. Unlike PRs, which survive only on glucose (sugar), the RPE may choose to consume either, a choice influenced by certain amino acids. “We hope we can manipulate those amino acids to encourage them to prefer fats over glucose,” says Dr. Miller. “This should have two benefits: increasing lipid consumption in the RPE and making more glucose available to the PRs.”
Another project will deactivate an enzyme critical to degrading (consuming) lipids, to test the theory that hindering the RPE’s lipid degradation will cause it to ‘spit out’ (secrete) what it can’t use. “When turning off that enzyme, we should see a corresponding increase in drusen deposits outside the RPE,” he explains. “The ultimate goal is to create a new model for testing future dry AMD therapeutics.”
