Advances in Retinal Research on Display at RD2014

Report from the XVI International Symposium on Retinal Degeneration

This research was supported by BrightFocus

There’s no mistaking the importance of a body part to which an entire meeting is devoted. The retina of the eye holds that distinction and was the focal point for 272 vision scientists gathered at the XVI International Symposium on Retinal Degeneration (RD2014) meeting held in Pacific Grove, California, last week (July 13-18).

An all-important part of the eye composed mainly of photoreceptor cells, the retina, in a nutshell, gives us sight.  Together its 6 to 7 million cone photoreceptors and 75 to 150 million rod photoreceptors sense and sort light, then transmit signals via the optic nerve that the brain interprets as images. Since there are fewer optic nerve fibers than photoreceptors, the transmission requires some convergence and mixing of signals into a visual mosaic. Not surprisingly, the retina’s complexity rivals that of the brain; in fact, the retina is essentially an extension of the brain into the eye.

Centering the retina is the macula, responsible for high-acuity vision, with its high concentration of cone cells contributing to high-resolution central vision. Thanks to both of these structures, humans have uniquely sharp and detailed vision that helps us perform sophisticated tasks. That detailed vision is what’s at stake with macular degeneration.

RD2014 provided a forum for BrightFocus-funded researchers to present the progress and results from their Macular Degeneration Research grants in oral presentations and posters. BrightFocus was the sole sponsor of the RD2014 poster session, featuring 159 scientific posters. Posters are one of the most powerful forms of knowledge exchange in the vision research community, where researchers have the ability to discuss their discoveries face-to-face with other experts in their field who might be from a lab located in the U.S. or in a country on the other side of the world. These discussions often set the stage for future breakthroughs in finding out what causes a disease, and accelerates the ability to get potential preventions and treatments to the clinic. The work of numerous BrightFocus grantees was on display. 

BrightFocus’ Scientific Program Officer, Diane Bovenkamp, PhD, was onsite to provide a first-hand account of RD2014, and she described a meeting where senior researchers made a point of seeking out younger colleagues in order to bolster their careers, share data, or just talk. “It’s a fantastic place for scientists to network and discuss scientific progress with others on a one-to-one basis,” she said. “Many attendees say it’s where fruitful collaborations start, as well as long-lasting friendships.”

Small and intimate meetings like this are fertile ground to further BrightFocus’ mission because they plant new research ideas and cross-fertilize work that’s already been done. Here’s Diane’s report of the BrightFocus-funded research presented at RD2014.

RD2014 Oral Presentations Featuring BrightFocus-Supported Research

Retina Waste Removal and Recycling Problems Can Lead To Age-Related Macular Degeneration (AMD) 

Title of Talk: Regulation of mechanistic target of rapamycin complex1 (mTORC1) signaling in retinal pigment epithelial cells; Authors: Mallika Valapala, Stacey Hose, Imran A. Bhutto, Rhonda Grebe, James T. Handa, Peter A. Campochiaro, Eric Wawrousek, J. Samuel Zigler, Debasish Sinha

Mallika Valapala, PhD, who’s part of the research team headed by 2014-16 BrightFocus grantee Debasish Sinha, PhD, at Johns Hopkins University, delivered a talk on behalf of the entire team. Dr. Valapala described their investigation into how an increased risk for AMD can be linked to problems with cell recycling and waste removal in the retinal pigmented epithelium (RPE), a single layer of cells situated at the back of the retina. Because of its high metabolic activity, the RPE is considered particularly vulnerable to breakdowns in both these forms of cellular housekeeping. 

There are many proteins involved with cell recycling and waste removal. In her presentation, Dr. Valapala reported evidence from their animal studies showing that when a particular protein (called mTORC1) was impaired, it interferes with these housekeeping functions. mTORC1 is considered to be a central sensor of nutrient status and wellbeing in cells, so treatments that renew its activity could be a new way to treat AMD. The laboratory will continue to study other potential therapeutic targets for the RPE recycling and waste removal process in Dr. Sinha’s BrightFocus grant. The National Eye Institute supported Dr. Valapala with a Young Investigator Travel Award to attend RD2014. Dr. Sinha is the 2014 recipient of the BrightFocus Carolyn K. McGillvray Award for Macular Degeneration Research.

Identifying Cell-Protective Drugs for the Treatment of AMD and Glaucoma (Results from Three BrightFocus-Funded Projects)

Title of Talk: High content screening to identify small molecules that promote the survival and differentiation of human stem cell-derived RPE cells; Author: Don Zack 

Donald Zack, MD, PhD, Johns Hopkins Wilmer Eye Institute, presented exciting results from his laboratory, and on behalf of PIs awarded two other BrightFocus grants for their research at Hopkins. The first project was from his 2011-13 BrightFocus grant, held with co-PI, Cindy Berlinicke, PhD, where they used an automated, robotic microscope image-based screening method to identify small molecule drugs that protect the retinal pigmented epithelium (RPE) cells as a way to treat dry AMD. The idea is that saving the RPE from dying, is a way to prevent the subsequent photoreceptor loss, since they depend on the RPE for maintenance and nourishment.  His team was able to identify a number of potent, protective molecules from a screen of hundreds of potential candidates.

Dr. Zack described those results as well as the findings from his 2012-14  National Glaucoma Research (NGR) BrightFocus grant using a similar screening method to find drugs that promote retinal ganglion cell survival as a way to treat glaucoma. This latter research grant was originally awarded to Zhiyong Yang, MD, PhD, and transferred to Dr. Zack in August of 2013 when Dr. Yang left Johns Hopkins. In addition, Dr. Zack presented results on behalf of Derek Welsbie, MD, PhD, the PI of another BrightFocus NGR research award from Johns Hopkins. Dr. Welsbie used a similar system of automated microscopes and robots to screen for a particular type of small molecules, called RNAi, to identify candidates that protect retinal ganglion cells in glaucoma.

RD2014 Posters Featuring BrightFocus-funded Research

New AMD Treatment Getting Closer To Clinical Trials

Title of Poster: IL-18 and its dichotomous role in age-related macular degeneration; Authors: Sarah Doyle, Ema Ozaki, Kiva Brennan, Marian Humphries, Kelly Mulfaul, James Keaney, Paul Kenna, Arvydas Maminishkis, Anna-Sophia Kiang, Ed Lavelle, Clair Gardiner, Padraic Fallon, Pete Adamson, Peter Humphries, Matthew Campbell

Matthew Campbell, PhD, of Trinity College, Dublin, shared the results of ongoing research investigating the safety and tolerability of increasing the levels of IL-18 as a treatment for wet AMD, which has advanced to testing in nonhuman primates. This is the continuation of research initiated in a BrightFocus grant to Peter Humphries, PhD, as principal investigator (PI), and Matthew Campbell as co-PI. Another current BrightFocus grantee, Sarah Doyle, PhD, also is an investigator on this project.

Two Targets for Treatment of Stargardt Disease—a Juvenile Macular Degeneration—Could Lead To Promising Treatments for Dry AMD

Title of First Poster: A potential therapy for bisretinoid-mediated retinal degeneration by modulating complement regulatory protein expression in the retinal pigment epithelium; Authors: Roxana A. Radu, Zhichun Jiang, Marcia Lloyd, Dean Bok, and Shanta Sarfare

Roxana Radu, MD, of the University of California, Los Angeles–Jules Stein Eye Institute presented her results that were supported by a 2008 BrightFocus MDR award. Dr. Radu is studying how the immune system (in particular, activation of the complement system) can lead to an abnormal, toxic buildup of Vitamin A products in the retinal pigment epithelium (RPE) in juvenile macular degeneration (Stargardt disease). She has identified a potential therapy to block the production of these toxic byproducts. The work has implications for treating dry AMD.

Title of Second Poster: Expression of mutant ELOVL4 in the absence of very long chain polyunsaturated fatty acids causes age-related functional and structural decline in rod but not cone photoreceptors; Authors: Martin-Paul Agbaga, Blake Hopiavuori, Feng Li, Nawajes Mandal, Richard S. Brush, Michael H. Elliott, Radha Ayyagari, Robert E. Anderson

Martin-Paul Agbaga, PhD, from the University of Oklahoma Health Sciences Center, presented findings on what happens in the retina of mice when a mutant form of the protein called Elongation of Very Long Chain Fatty Acids (ELOVL)4 is expressed, causing a type of Stargardt’s disease. He discovered that there are age-related declines in the structure and functions of rod but not cone photoreceptors. He received the 2013 BrightFocus Elizabeth Anderson Award for Macular Degeneration Research for this grant. The National Eye Institute supported Dr. Agbaga with a Young Investigator Travel Award to attend RD2014.

Less Efficient Cholesterol Clearance by Certain Forms of ApoE Protein Increases Risk of AMD

Title of Poster: ApoE in the RPE: can isoform-specific actions contribute to cellular pathology; Authors: Kimberly A. Toops, Li Xuan Tan, Aparna Lakkaraju

Kimberly Toops, PhD, a Postdoctoral Fellow in the lab of BrightFocus grantee Aparna Lakkaraju, PhD, of the University of Wisconsin - Madison, presented that group’s results showing that apolipoprotein E (ApoE) in the RPE contributes to the cause of disease. ApoE is a protein transporter involved in cholesterol clearance from cells. Individuals with the ApoE2 allele/subtype are at increased risk for AMD and ApoE4 is protective. (A curious note is that for Alzheimer’s disease, the reverse is true—ApoE4 confers greater risk and ApoE2 is protective.) The team is looking for explanations as to why, in AMD, ApoE2 protein is less efficient at clearing out cholesterol, and why excess cholesterol slows down ApoE2 trafficking, but not ApoE4 or E3 trafficking in AMD. The National Eye Institute supported Dr. Toops with a Young Investigator Travel Award to attend RD2014.

Monkeys Given “American-Style” Low Nutrient, High Fat/Calorie Diet Develop Retina Problems Resembling Dry AMD In Humans

Title of Poster: Drusen progression, influence of diet and correlation with cone density in a Japanese macaque model of maculopathy; Authors: Trevor J. McGill, Laurie M. Renner, Anda Cornea, Mark E. Pennesi, Travis B. Smith, Kay Rittenhouse, Joachim Fruebis, Martha Neuringer

Trevor McGill, PhD , of Oregon Health and Science University, presented how their group looked at drusen progression in a Japanese macaque monkey model of maculopathy, including the influence and correlation of diet with cone density. The work involves many cutting-edge imaging techniques, including adaptive optics, cone density measurements, and method to count the number of drusen. Dr. Neuringer was co-PI on a 2009 BrightFocus MDR award.