We reached out to a University of California, San Francisco clinician and researcher to get her take on the quickly evolving research landscape and the growing mandate for genetic testing.
Dr. Jacque Duncan is an ophthalmologist at the University of California, San Francisco (UCSF). As a retinal specialist, she is particularly focused on taking care of patients with inherited retinal diseases (IRDs). Dr. Duncan’s work as a translational researcher is moving the field of retinal medicine forward and giving her the opportunity to apply her findings in the clinical care and insight she offers her patients.
Q: What is your area of expertise and what area of science are you pursuing when it comes to genetic disease?
A: I'm interested in the clinical characterization of patients with inherited retinal degenerations and using novel imaging modalities to understand how different mutations affect photoreceptor survival. In other words, I take care of patients with retinal degenerations and I work with geneticists to help figure out what their mutation is, if we can.
Once we figure out what the mutation is, then we do a series of tests to try and better understand what's happening to their retina in response to these mutations. We use tests of their vision—such as measuring their visual acuity and visual fields—and we measure how sensitive their retinas are to light with electroretinography (ERG) tests. And then we take pictures of their retinas to see how the eyes appear to be affected by the disease.
I work with a scientist from University of California, Berkeley (UC Berkeley) to get special images of the retina that let us look at the individual vision cells—which you can't really see with other techniques—to see how many of the cells have been lost and how many still remain.
Q: What do you use to look at the loss of photoreceptor cells?
A: We use a couple of different approaches. We take color fundus photographs, which are widely available in most ophthalmologists’ offices, and we take side views of the retina using pictures called optical coherence tomography, or OCT scans. Those are also available in most ophthalmologists’ offices, but OCT scans can't see the individual vision cells themselves. They don't have the resolution needed to identify individual vision cells, which include the cones (the daytime, central, and color vision cells) and the rods (the nighttime and peripheral vision cells).
We look at the cells using a technique developed by my collaborator Austin Roorda, PhD (along with his colleagues) at UC Berkeley. He holds a patent on this technology called “Adaptive Optics Scanning Laser Ophthalmoscopy” that allows us to correct for subtle irregularities in the image so that we can see individual vision cells.
Q: How will that kind of testing be used in the rapidly evolving field of gene therapy research?
A: We're trying to understand how photoreceptors are affected by degeneration. Once we understand that clearly, then we may be able to use these same approaches to see how things are changing in response to a therapy, whether that be gene therapy, neurotrophic factor therapy, small molecule therapy, stem cell therapy, or any other kind of therapy. It's a very exciting time for the field, and I think that our research may provide us with sensitive ways of looking at how different potential treatments might affect photoreceptor survival.
Q: How have these sorts of advances changed the conversation you have with your patients?
A: I have been fortunate to work in this field over the last 17 years, and the current era is a very exciting time for patients with inherited retinal diseases. Certainly, we know a lot more about the genetic causes of different types of retinal degenerations, and that provides opportunities to understand the mechanisms by which photoreceptors are being affected and not surviving—which may lead to potential therapies. I think it's always very rewarding to sit down with patients to explain the cause of their disease and how a potential treatment may modify its course to try and keep their vision cells alive longer. Recent developments in the field continue to provide new understanding of how potential treatments may preserve vision.
Q: There are plenty of people who have been told, “You’re going to go blind and there is nothing we can do.” In despair, some of them have even stopped seeing their ophthalmologist or retinal specialist. Does that message need to change for people diagnosed with an IRD?
A: I think that there's a lot of reason for optimism, and certainly a lot of reasons to try and find out what the cause of disease is because the more people know about what they have, the better.
Also, the more the community of ophthalmologists knows, the better eye care providers are able to care for patients affected with retinal degenerations. Understanding the cause of a patient’s disease may help identify which clinical studies to participate in and help the patient better understand the progress and severity of their disease, as well as the disease progression timeline.
About a year ago I worked with a group of retinal degeneration specialists to provide a guidance document that we have had posted on the American Academy of Ophthalmology website saying, "Here's the standard of care today, for people with inherited retinal degeneration. Here's how you should take care of patients with retinal degenerations, here's what testing they need, here's what you should be telling them." This was also posted to the American Society of Retina Specialists website.
We're hoping to raise awareness and spread greater understanding of the changes in the field because until things really change—in terms of therapies being available for patients—it's a little hard to get their attention of eye care providers.
Q: Do you think patients are returning to their eye care specialists with questions about all of the research being done?
A: Oh, certainly. Well, my patients are coming to my clinic with a lot of questions! My patients tend to be pretty knowledgeable and they have done a lot of research already about what they have. They have had to since their eye care providers may not necessarily have seen patients with what they have. So, my patients do have a lot of questions and come well-informed, in my experience.
Some patients who are newly referred to me, however, just want more information about what they have. I don’t think many people feel fully informed about the disease they’ve been diagnosed with—and they are appreciative when they hear more about what might be causing their vision loss.
Q: How has genetic testing changed over the last 5 or 10 years? What are the implications for patients and physicians?
A: That's a great question. Next-generation sequencing panels have become more widely available and more accessible for patients. The challenge remains that insurance won't pay for most of these. Some panels have more genes represented in them than others. We often do testing through a number of different labs that are providing really great comprehensive panels that include testing for a lot of different genes associated with retinal degenerations from the RetNet website.
With testing comes a really strong need for genetic counseling—to understand the results when they come back—because many times we see patients who have only one gene mutation, when two of the same gene mutation are really necessary for disease. Or we see patients who have variants of unknown significance because it's a mutation that has never been reported before in any other patients. It's uncertain whether it's necessarily the cause of the patient's disease or whether there's something else we haven't found yet.
However, with great opportunity comes great responsibility. I think we have a lot more opportunity to identify genetic changes in patients, and it's much more likely today that we'll find a mutation than it ever was in the past. Often, the results of genetic testing are very complicated to interpret, so I think we benefit tremendously from working closely with genetic counselors.
Q: Why is it important for a patient to understand their genetic mutation?
A: It’s important to learn as much as possible about a patient's mutation. Some mutations impact proteins expressed in the retinal pigment epithelial cells, other mutations impact proteins expressed in rods, and still others affect proteins expressed in both rods and cones. The more you know about what you have, the more likely you are going to be able to realize which research and potential therapies may be appropriate for you to follow.
The other reason that genetic testing and counseling is important is to best understand how this disease is being inherited in a family—to give the patient the most accurate possible information about potential risk to other family members. Genetic testing can often provide insight into that.
Q: What is the connection between genetic testing and participating in IRD clinical trials?
A: There are over 20 clinical trials currently enrolling patients—which was not the case many years ago. Many of those clinical trials require that you understand what kind of disease you have, what the genetic cause is, and at what stage the disease is. For that reason, I think it's valuable to work with an expert in inherited retinal degeneration or a retinal specialist that actively sees patients with IRDs to get as much information as you can about the disease affecting you or your family member. That way you can be informed about which research trials might be most appropriate for you or your family.