Aparna Lakkaraju, PhD, Associate Professor, University of California, San Francisco, School of Medicine
Research in the Lakkaraju laboratory builds on fundamental insights from retinal cell biology to develop effective therapies for inherited and age-related macular degeneration (AMD). The initial site of injury in AMD is the retinal pigment epithelium (RPE), the tissue that nourishes and supports the photoreceptors, the light-sensing cells of the eye. Early clinical features of AMD are RPE abnormalities and the accumulation of insoluble aggregates (drusen) above and beneath the RPE. Over time, continued damage to the RPE and formation of these aggregates sets in motion a vicious cycle that eventually results in vision loss in AMD.
Several genes and environmental factors have been implicated in influencing susceptibility to AMD. However, little is known about mechanisms that bring about RPE damage, how this leads to aggregate formation, and how genes implicated in AMD participate in these processes to destroy vision. Dr. Lakkaraju’s research team investigates mechanisms that regulate RPE homeostasis such as cellular clearance, mitochondrial function, inflammation and immune privilege in the retina.
With funding from her AMDF/RPB Catalyst Award, in the amount of $300,000, in a project entitled “Novel approaches to identify tipping points and therapeutic targets for early AMD,” she investigated how two major genetic risk factors in AMD act as “tipping points” to initiate RPE injury, and how these tipping points drive the formation of the drusen that eventually lead to AMD:
“Over 50 independent genes are associated with AMD. These genes regulate important pathways such as complement activation, cholesterol metabolism and oxidative stress. The complement pathway is responsible for controlling inflammation and the immune response. Despite a wealth of data implicating increased complement activation in AMD, drugs that prevent complement activity have failed in clinical trials. Our studies link complement activation, lipid accumulation, and drusen deposition with mitochondrial injury, and we have found that small molecule drugs that act upstream of complement and lipids can protect / reprogram RPE mitochondria and prevent drusen nucleation, suggesting a novel therapeutic target for AMD.”
Note: This publication does not accurately cite AMDF support, which is provided through the acknowledged Research to Prevent Blindness Catalyst Award for Innovative Approaches to AMD.
Apolipoprotein E isoform-specific phase transitions in the retinal pigment epithelium drive disease phenotypes in age-related macular degeneration