Foundation Invests $1.5 Million to Find Elusive RP Genes

May 08, 2014

For every person affected by an inherited retinal degeneration such as retinitis pigmentosa (RP), a mutated gene is at the heart of his or her vision loss. These mutations are like misspellings in a recipe, but even the smallest mistake can have devastating consequences. It can cause retinal cells to make a defective protein, or the wrong amount of one; subsequently, the cells die and vision is lost.

Identifying a patient’s mutated gene is essential to making a definitive diagnosis, which may direct him or her toward emerging treatments that will someday improve vision. A genetic diagnosis may also be necessary for participating in clinical trials.

Finding these mutations has never been easy, because inherited retinal diseases are rare. But thanks to advances in disease knowledge and gene-discovery technologies, mutations in more than 200 genes have been linked to retinal degenerations. Funding of dozens of genetic researchers from the Foundation over the past 25 years has played a major role in identifying these genes.

While the success rate varies depending on the disease and inheritance pattern, genetic testing still only reveals the disease-causing gene in about 50 percent of cases. Researchers believe that dozens of retinal-degeneration genes remain undiscovered because they are ultra-rare, the types of disease-causing defects are unusual or they’re in genetic regions where problematic mutations are less likely to occur.

To find more elusive RP genes, the Foundation is investing $1.5 million in a collaborative project to develop a new discovery approach. The hope is that the approach — which involves whole genome sequencing (WGS) and induced pluripotent stem cells (iPSCs) — can be effectively used, and continually enhanced, by other scientists working on retinal gene discovery.  

One of the funding recipients is Eric Pierce, M.D., Ph.D., who is chairman of the Foundation’s Scientific Advisory Board and director of the Ocular Genomics Institute at Massachusetts Eye and Ear Infirmary. He is conducting WGS studies of families with RP, which involves looking deep into each person’s genome and scanning as much as 97 percent of his or her DNA to find mutations that potentially cause disease.

The challenge of WGS is that it invariably uncovers thousands of genetic variations, and it can be difficult — as well as expensive and time-consuming — to figure out which ones are causing a disease. So Dr. Pierce will also study the RNA — the genetic messages created from DNA — of the RP patients’ cells to identify potential disease-causing abnormalities.

The other recipient is David Gamm, M.D., Ph.D., at the University of Wisconsin-Madison. He will provide Dr. Pierce with the retinal cells by taking samples of patients’ skin or blood, genetically tweaking the cells so they revert back to a stem-cell state, and then coaxing them forward to become retina. Known as iPSC, the cells are derived through a technique Dr. Gamm is also using to develop retinal cell transplantation therapies for restoring vision.

Dr. Pierce can also use Dr. Gamm’s iPSC-derived retinal cells from patients to study the effect of disease-candidate mutations he’s identified through WGS.

“While we hope that this project will lead to the discovery of new RP genes, the ultimate goal is to optimize and standardize the novel approaches being developed by Drs. Pierce and Gamm so they can be used more widely,” says Stephen Rose, Ph.D., chief research officer at the Foundation. “This work won’t change the genetic discovery landscape overnight, but it is a good starting point that will no doubt provide us with strong momentum for moving forward.”