Ed Stone, Val Sheffield, Tom Casavant, and their colleagues at the University of Iowa’s Center for Macular Degeneration and Allied Retinal Diseases see no reason why there shouldn’t be cost-effective, efficient, and accurate genetic testing available for every person who has an inherited retinal degenerative disease (RDD). They’re certain that more and better treatments will be attainable, if genetic testing — and the information gleaned from it — is more accessible to researchers, ophthalmologists, and patients. With support from The Foundation Fighting Blindness and other organizations, they are well poised to make this plan for ubiquitous testing a reality.
Stone, an ophthalmologist and inherited retinal disease expert, and Sheffield, a pediatrician and geneticist, combined their talents in the early 1990s to map and/or identify a number of genes involved in inherited eye disease. Their first discovery, in 1992, was the chromosomal location of the gene that causes Best disease, an inherited form of macular degeneration characterized by a loss of central vision. In 1994, Tom Casavant, an engineer who had worked for more than 10 years in the area of high performance parallel computing, joined the group to help take advantage of the huge amount of molecular information that the human genome project and other similar efforts were making available to the scientific community.
More genetic discoveries relevant to RDDs followed, including the identification of five of the genes that cause Bardet-Biedl syndrome (a disease that includes symptoms such as retinitis pigmentosa, diabetes, obesity, as well as developmental and cognitive disabilities). In 2004, they discovered that the fibulin5 gene is involved in a small fraction of typical cases of age-related macular degeneration.
The Center has grown to include more than 100 individuals distributed across six different departments and four different colleges of the University. With expertise in a wide range of areas including internal medicine, genetics, molecular biology, computer engineering, biomedical engineering, and statistics, the Center’s faculty and staff are well-equipped to focus on genetic research and testing, which requires multidisciplinary teamwork and a lot of person-power. The discovery of fibulin5, for example, involved a team of more than 25 different individuals working together for more than 3 years.
In addition to gene discovery work, the Center conducts research on gene- and cell-based therapies for treatment of RDDs. They also have a large clinical unit that takes care of people with age-related macular degeneration and other retinal diseases. Through their clinical work, they’re able to evaluate medical and pharmacological therapies, as well as operative techniques. Also on the clinical side, the Center offers low vision rehabilitative services, retinal photography and angiography, optical coherence tomography, electrophysiology and perimetry. These capabilities will likely play an important role in the future evaluation of new treatments for RDDs.
Stone sees the expansion and proliferation of genetic testing as the next big step forward for the Center, as well as for the entire community of people affected by inherited RDDs. During the 1990s, he had expected that with the advent of many gene discoveries, commercial entities would soon get into the genetic testing business and provide tools that would make testing for inherited retinal diseases easier. "I imagined that different diagnostic companies would develop tests, and clinicians would just order them," he says. "But that just didn’t happen, because of financial, technological, and intellectual property obstacles…exacerbated by the fact that the diseases are so rare."
Convinced that they needed a nonprofit, nonproprietary, fee-for-service testing strategy, the Center created the Carver Laboratory for Molecular Diagnosis (www.carverlab.org) two years ago. Now they’re partnering with a number of groups around the country — including the FFB — to develop tests that can be delivered affordably and effectively on a national scale.
Stephen Rose, chief research officer at FFB, is in strong agreement with the need for readily available genetic testing along with centralized collection and analyses. "The Foundation is very supportive of this approach, because it will lead to meaningful results and treatments for patients. We are pleased that researchers at the University of Iowa are stepping up to the plate with a strategy that emphasizes collaboration and inclusion — it is the best way to move forward," says Rose.
Large-scale genetic testing offers key benefits to patients, researchers, and physicians. As Stone says, "The only way you can determine if a mutation is responsible for disease is by studying large groups of patients and keeping track of the results." Stone, Sheffield and Casavant want to build a database to track every sequence variation found, and even those variations that aren’t necessarily helpful in treating retinal degenerative diseases, because they might be useful to other researchers studying other diseases. "We are modeling this after the strategy of the Human Genome Project. In that effort, researchers were required to share their findings and this sharing proved to be a great benefit to everyone — you got way more back than you ever had to give," he says.
The aggregated patient information would also be helpful in identifying participants for clinical trials. Getting the right people, and enough of them, is often a challenge in conducting a clinical trial, especially when the study is for treatment of a rare condition.
Crucial to the identification of potential study participants will be the development of a series of genetic tests that can be administered easily and cost-effectively in an ophthalmologist’s office. Stone says that this method of testing would empower both the patient and doctor, giving them more opportunity to learn about the disease, including the availability of clinical trials. Patients with positive test results will be able to use tools such as the Internet to track the latest information on their specific disease. With the guidance of the physician and a genetic counselor, patients can also make more informed decisions about family planning and career choices.
Stone adds that testing breakthroughs need to go beyond those that are just technological. "To the degree that a clinician can correctly narrow the list of diagnostic possibilities before a test is performed, fewer genes need to be screened, and there is a higher likelihood of finding an answer faster and less expensively," he says.
The word "registry" is often batted around as the term for this centralized, genetic clearinghouse. But Stone shies away from it, because “registry” implies that the patient is signing up for something. He emphasizes the need to protect the patient’s privacy. "In our zeal to make progress in these diseases, we need to have a way to shield patients from unwanted intrusion…in 5,000 years of medicine, we’ve done it through the doctor-patient relationship. In most cases, personal information should remain with a doctor, and it is a doctor or another trained professional who informs the patient of results," he says.
What Stone and other genetic researchers are most interested in is collecting information on genotypes and phenotypes of large populations of people with inherited retinal degenerative disease. A person’s genotype is essentially their genetic makeup — how their inherited disease appears genetically. Their phenotype is how their inherited condition appears physically (i.e., degree of vision loss, how quickly loss of vision is progressing, what vision is preserved, etc.). By collecting large amounts of this disease-related data, researchers are better able to identify the mutations that cause vision loss, and ultimately, better treatments, cures, and preventions.
DISCLAIMER: Physicians differ in their approach to incorporating research results into their clinical practice. You should always consult with and be guided by your Physician’s advice when considering treatment based on research results.