Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Penn team characterizes the underlying cause of a form of macular degeneration

20.04.2017

Named for Friedrich Best, who characterized the disease in 1905, Best disease, also known as vitelliform macular dystrophy, affects children and young adults and can cause severe declines in central vision as patients age. The disease is one in a group of conditions known as bestrophinopathies, all linked to mutations in the BEST1 gene. This gene is expressed in the retinal pigment epithelium, or RPE, a layer of cells that undergirds and nourishes photoreceptor cells, the rods and cones responsible for vision.

Despite the century of work on bestrophinopathies and the identification of genetic mutations responsible for the conditions, no one had identified the underlying mechanism that led to the vision loss seen in Best disease until now.


The Penn-led research team characterized the underlying mechanism that leads to the blinding Best disease; a loss of the microvilli that support and "feed" photoreceptor cells. The contrast can be seen above, with a normal retina on the right and an affected on on the left.

Credit: University of Pennsylvania

Using an animal model of Best disease in combination with biochemical and optical assays, a team of researchers at the University of Pennsylvania has pinpointed a number of abnormalities that give rise to the impairments seen in the disease.

"The genetic cause of the disease has been known for 20 years, but no one had samples of patients at the stage when the disease starts," said Karina E. Guziewicz, research assistant professor of ophthalmology in Penn's School of Veterinary Medicine and lead author on the study. But "we were now able to pinpoint this early stage and find out what factors trigger the development of lesions."

The new information sets the team up for testing a gene therapy to treat the disease, as the researchers will be able to observe whether or not these structural and biochemical abnormalities have been corrected.

"Now that we understand what we're seeing, it allows us to judge the success of a particular therapy," said Gustavo D. Aguirre, professor of medical genetics and ophthalmology at Penn Vet.

Kathleen Boesze-Battaglia, a professor in the Department of Biochemistry in Penn's School of Dental Medicine, also contributed her expertise in lipid biochemistry and spectral analysis of lipid debris to the study, which was published in the journal Progress in Retinal and Eye Research, the top ranked journal in the eye-research field.

"Interestingly, the lipid debris accumulation is similar to cholesterol rich plaque formation, compounded by a complexity of vitamin A metabolism," said Boesze-Battaglia. "Alterations in lipid metabolism likely contribute to the secondary disease pathology in this model."

The main puzzle surrounding Best disease was why, despite the BEST1 gene being mutated in the RPE throughout the retina, vision loss struck the macula and fovea, the central areas of the retina responsible for reading and tasks requiring high-resolution vision, while seeming to spare the rest. Researchers had observed lesions in this area, but it was unknown why they developed.

In this study, the Penn-led team discovered that this predilection of the macula to develop lesions has to do with differences in the supporting structures of rods versus cones.

Rods, which make up more than 90 percent of photoreceptor cells in the retina and are responsible for dim-light vision, have a cluster of supporting structures known as RPE microvilli that cup the cell like stakes holding up a plant. In contrast, cones, the color-sensing photoreceptors that make up 3 to 5 percent of all photoreceptors but are overrepresented in the macula, are engulfed in a sheath of microvilli. In addition, cones are supported by an insoluble matrix.

Examining cross-sections of the fovea-like region in the canine macula of dogs affected with the canine equivalent of Best disease, the researchers found that the microvilli don't form and that the matrix is fragmented. The susceptibility of the macula is due to the fact that cones are the predominant cell type there and rely on the matrix for support and nutrient exchange.

"We were not expecting to find such dramatic structural abnormalities," Guziewicz said. "For a hundred years, this has been thought to be a disease of the RPE, but we have now identified this as a disease of the RPE-photoreceptor interface."

"The RPE provides transport of nutrients to the cones and engulfs the discarded part of cones and rods," said Aguirre. "When you lose the matrix, you lose the connection between those cells and the RPE and that leads to disease."

To determine if the same would be true in humans, the researchers looked at human induced pluripotent stem cell-derived RPE from Best disease patients and found similar signatures: microvilli numbers were decreased in length and density. These experiments were conducted in collaboration with David Gamm's laboratory from the McPherson Eye Research Institute at the University of Wisconsin-Madison.

Looking ahead, the research team would like to continue to probe the biochemical signals that lead to the improper development of the microvilli and matrix and push ahead with developing and testing a gene-therapy approach to treating bestrophinopathies.

"Knowing where the disruptions occur will allow us to develop proper outcome measures for a gene therapy, which is in the works," said Guziewicz.

###

The paper's other authors were Penn Dental Medicine's Néstor M. Gómez and Anuradha Dhingra, Penn Vet's Kathryn Zorych and Emily V. Dutrow, the University of Wisconsin-Madison's Divya Sinha and David Gamm and the University of Iowa's Robert F. Mullins and Edwin M. Stone.

The research was supported in part by the Foundation Fighting Blindness, the Macula Vision Research Foundation, the National Eye Institute, Research to Prevent Blindness, the Retina Research Foundation, the Van Sloun Fund for Canine Genetic Research and Hope for Vision.

Media Contact

Katherine Unger Baillie
kbaillie@upenn.edu
215-898-9194

 @Penn

http://www.upenn.edu/pennnews 

Katherine Unger Baillie | EurekAlert!

More articles from Health and Medicine:

nachricht 3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg

nachricht Better equipped in the fight against lung cancer
16.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Research reveals how order first appears in liquid crystals

23.05.2018 | Life Sciences

Space-like gravity weakens biochemical signals in muscle formation

23.05.2018 | Life Sciences

NIST puts the optical microscope under the microscope to achieve atomic accuracy

23.05.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>