Insight Into the Formation of Harmful Deposits In the Retina

Aparna Lakkaraju, PhD
University of Wisconsin System (Madison, WI)

Co-Principal Investigators

Kimberly A. Toops, PhD
University of Wisconsin-Madison (Madison, WI)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2017
Disease:
Macular Degeneration
Award Amount:
$160,000
Grant Reference ID:
M2015350
Award Type:
Standard
Award Region:
US Midwestern

Recipient of The Charlotte and Alexander Danilevsky Memorial Award.

Can RPE-Derived Exosomes Contribute to Subretinal Drusenoid Deposits?

Summary

Millions of Americans currently suffer from age-related macular degeneration (AMD), the most common cause of irreversible vision loss among older adults. With age, insoluble aggregates accumulate above and beneath the retinal pigment epithelium (RPE), the tissue that nourishes and supports the photoreceptors, the light-sensing cells of the eye. Over a lifetime, these aggregates conspire with environmental and genetic factors to damage the pigment epithelium and lead to a chronic decline in central focused vision (ie, the type of vision supported by the macula). Our work seeks to understand how these aggregates form, how they impact cell function, and whether a promising treatment strategy recently identified by our group will help prevent the formation of these aggregates and preserve healthy vision.  

Details

A key feature of age-related macular degeneration (AMD) is the accumulation of cellular debris or garbage within and around the RPE, the layer of cells that nourishes and supports the light-sensing photoreceptors. The presence of debris called drusen beneath the retinal pigment epithelium (RPE) has long been used to monitor the progression of AMD. Recent advances in non-invasive imaging techniques have revealed that drusen are also present above the RPE in the eyes of people with AMD. These deposits, called sub-retinal drusen, are now associated with irreversible vision loss seen in advanced AMD. Nothing is currently known about where these deposits originate, how they form and how they cause vision loss.
 
Dr. Lakkaraju proposes to investigate whether these deposits originate from stressed RPE in the form of small bubbles called exosomes, which can get trapped between the RPE and photoreceptors to “seed” sub-retinal drusen. Her group plans to create a “disease in a dish” model to follow the release of exosomes by the RPE in real time, using live imaging. They will also investigate whether unhealthy RPE cells release exosomes that can promote inflammation in the retina.

Recent work from Dr. Lakkaraju’s group has identified FDA-approved drugs that help clear garbage and prevent inflammation in the RPE. The second part of this project will evaluate the potential of these drugs to prevent the release of these harmful exosomes from the RPE.

The release of harmful exosomes is also thought to contribute to Alzheimer’s and Parkinson’s diseases. However, the role of RPE exosomes in AMD has been largely unexplored due to the technical challenges associated with studying these bubbles in vivo. Dr. Lakkaraju’s disease in a dish model is a novel and innovative approach that has not been attempted to date. It will be used to test FDA-approved drugs that have documented safety profiles in humans. These agents can reach the brain after oral administration, so they could reach the retina in therapeutic concentrations without the need for invasive drug delivery. Successful completion of these studies will establish the potential of these drugs as therapies that could benefit millions of AMD patients worldwide. 

About the Researcher

Aparna Lakkaraju, PhD, is an assistant professor in the Department of Ophthalmology and Visual Sciences at the School of Medicine and Public Health at the University of Wisconsin-Madison. She is an affiliate in the Division of Pharmaceutical Sciences and also holds the Retina Research Foundation/McPherson Eye Research Institute Rebecca Meyer Brown Professorship. She earned her B. Pharm degree from Kakatiya University, India, and her PhD from the University of Minnesota, Minneapolis. She completed her post-doctoral training at the Weill Medical College of Cornell University in New York City. Dr. Lakkaraju’s team focuses on understanding the mechanisms that contribute to vision loss in AMD. Her group uses state-of-the-art high-speed, high-resolution live imaging of healthy and diseased RPE to identify the earliest defects that could contribute to vision loss in AMD. This information is then used to discover novel therapies for this devastating disease. 

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