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Kimberly Drenser, MD, PhD, explains that there is hope for treating these patients with the advent of viral-mediated, gene replacement therapy and new synthetic replacement molecules for inherited retinal degenerations.
Settling for the appropriate tests and the management of retinal degeneration is frustrating and the process can be complicated by the absence of satisfactory treatment options for patients with these diseases.
However, Kimberly Drenser, MD, PhD, pointed out that there is hope for treating these patients with the advent of viral-mediated, gene replacement therapy and new synthetic replacement molecules for inherited retinal degenerations.
“We test because we know that there is a cause and effect between a gene and a mutation,” said Dr. Drenser, director of ophthalmic research, Beaumont Eye Institute, Oakland University, Royal Oak, MI.
“There is a high correlation between an alteration in a gene and disease. The most important point is that we want to know that there is something we can do with that information to have an effective intervention or therapy.”
In some cases, there is a degree of urgency for testing with a patient who is planning a family and has a strong family history of a retinal degeneration.
In other cases, there is less immediacy attached to testing.
However, decisions must be made about how often patients are evaluated and the type of testing that is performed.
Other choices include decisions about patient observation, surgical intervention, or other options. What is more important, she noted, is patient referral to a treatment center or a clinical trial.
One approach is gene therapy. For eye diseases, recombinant, adeno-associated viral (AAV) vectors can be used to transfer genetic information to a host cell. There are a number of advantages to this approach. The most notable of which is safety.
“A plasmid is used that mimics what the virus looks like, but the gene of choice can be inserted and a helper gene is used,” Dr. Drenser explained. “This system creates what looks and acts like a virus and the gene of choice is transferred to a host cell to fix the disease.”
A gene therapy to treat Leber’s congenital amaurosis and retinitis pigmentosa gene mutations is available (rAAV-RPE65, Spark Therapeutics). The National Eye Institute and Applied Genetic Technologies Corp. are conducting two clinical trials of rAAV-RS1 to evaluate the replacement therapy for treating congenital X-linked retinoschisis.
Dr. Drenser and colleagues are involved in gene testing of these retinopathies.
“The more we study these retinopathies, the more we understand how important these are to managing these patients,” she said.
Dr. Drenser presented an example of a patient with a mild familial exudative vitreoretinopathy.
She explained that in compared to a patient with a severe retinal detachment that is complex in nature, “these scenarios are all called the same thing, but they obviously act very differently.”
Gene testing also can direct the management of these patients. Dr. Drenser recounted that an analysis of patient characteristics showed that 44% had a mutation of the major receptor and another 44% had a ligand mutation.
This information affects the treatment choices.
“The ligand mutations require the fewest amounts of laser or anti-vascular endothelial growth factor (anti-VEGF) treatments, possibly because the disease is stable following the initial treatment,” she said.
In contrast, Dr. Drenser added, patients with a mutation of the major receptor have the greatest need for recurrent treatments to manage exudation.
Interestingly, patients with mutations in multiple genes have the greatest need for surgery and repeated surgery.
The important message is that the availability of information about specific gene mutations is beginning to guide treatment and management of these retinal diseases.
Another noteworthy realization is that knowledge of specific gene mutations may predict retinopathy of prematurity (ROP). The same genetic analysis showed that 10.6% of children with ROP had mutations in a major receptor.
“This has great implications for having higher centers of care if we can use genetic testing to identify children who are at risk of ROP,” Dr. Drenser said.
So when determining which tests to order, the differential diagnosis is key. This can be the most frustrating process.
Dr. Drenser recommended the GTR website of the National Center for Biotechnology Information through the National Institutes of Health. On the website, when the disease or gene of interest is plugged in, the site helps direct the user to appropriate laboratories.
Kimberly Drenser, MD, PhD
This article was adapted from Dr. Drenser’s presentation, “What, When, and Why to Test for Retinal Degeneration,” at the Retina Subspecialty Day during the 2015 American Academy of Ophthalmology meeting.