In this episode of Evidence-Based Retina, Rishi P. Singh, MD, FASRS, and Aaron Nagiel, MD, PhD, discuss why diagnosing and treating inherited retinal disease is so challenging. They explain why getting answers often takes years, discuss the limitations of genetic testing, and explore easy ways that clinicians can support their patients.
Dr. Nagiel is an assistant professor of clinical ophthalmology at the Keck School of Medicine at USC. He’s also an attending physician in the vision center at the Children’s Hospital of Los Angeles. When he isn’t teaching or seeing patients, Dr. Nagiel leads a research program designed to develop better ways to treat pediatric retinal diseases through novel treatments, including stem cell-based and gene therapies.
Realities of IRDs fast facts:
- IRD patients often experience difficulty receiving an accurate diagnosis.
- Genetic testing can help identify the underlying causes of IRD, but because there are so many types, it has limitations.
- IRDs affect every patient differently. As a result, people with the same diagnosis may experience very different symptoms and levels of severity.
- A genetic diagnosis isn’t a cure-all, but it can help patients better understand their condition and determine their eligibility for clinical trials and treatments.
- Advances in gene-based therapies offer hope and potential treatment options for even the most complex IRDs.
Deeper dive: Realities of inherited retinal disease
Dr. Singh and Dr. Nagiel explained that although IRDs affect millions of people worldwide, diagnosis and treatment can be challenging. Symptoms vary from patient to patient, and even people with the same diagnosis can experience the condition in vastly different ways.
Despite these nuances, clinicians who educate themselves can help patients get the answers and support they need.
Getting an IRD diagnosis is often a lengthy process
IRDs are relatively rare, but they can have outsized impacts on patients and their families. Because they range in severity and symptom profile, receiving a diagnosis often takes a significant amount of time. According to one study, the average time to diagnosis was 15 years.1
“It’s very difficult sometimes for these patients to get a proper diagnosis…even in the best-case scenario. We have only about a 75% hit rate on [the] most advanced genetic testing platforms, and so that still leaves 25% of patients who know they have something wrong…but they don’t get a real label.”
Dr. Nagiel shared his experience treating several children with RPE65-associated retinal disease. These patients began experiencing symptoms at an early age, but doctors attributed them to other conditions, such as autism. Some of these children even underwent brain MRIs or extensive genetic panels, but because those panels didn’t include the relevant genes responsible, their families still waited years to receive a correct diagnosis.
Clinicians who are able to recognize the symptoms of IRDs can help point patients in the right direction and may even speed up the diagnostic process.
Genetic testing can provide answers, but obstacles exist
Dr. Singh and Dr. Nagiel noted that genetic testing has made diagnosing IRDs easier, but it isn’t a guaranteed solution either. Consider that 51% of patients in one study with a suspected IRD received an incorrect initial diagnosis.2
Even when the results of genetic testing are correct, accessing those tests can be challenging due to factors such as:
- Availability and cost
- Insurance coverage or denials
- Differences among commercially available testing panels
- Certain genes being omitted from some panels
Clinicians may even present barriers themselves. Not everyone has the training to know which type of genetic test is appropriate or feels comfortable interpreting genetic test results. So they may make an inaccurate recommendation or refer their patients to other providers, pushing a diagnosis further out.
A genetic diagnosis doesn’t tell the full story
“We’re taught RPE65 is LCA. They’re all blind...this disease has this...this disease has that. But once you get into the thick of things, you realize there’s an enormous spectrum.”
Sometimes, clinicians who aren’t well-versed in IRDs assume that identifying a specific gene or gene variant will make it easier to confirm a diagnosis. This makes sense in theory, but IRDs are incredibly complex and exist along a spectrum. Dr. Nagiel even noted that patients with similar mutations, including family members, may experience different levels of disease severity.
He shared the fascinating story of a patient in his 40s with pathogenic RPE65 variants who retained 20/20 vision and a normal-looking macula. This patient’s most noticeable symptom was nyctalopia, so he didn’t drive at night.
Because of factors such as modifier genes, gene variant differences, and incomplete penetrance, clinicians should avoid making broad assumptions based solely on a patient’s genetic diagnosis. Approaching each patient on a case-by-case basis is a great place to start.
Why a proper diagnosis matters beyond patient care
Advances in genetic testing have made it easier to diagnose IRDs, but the benefits go beyond simply labeling a disease. With a proper diagnosis in hand, patients can better understand their symptoms, more effectively plan for their future, and understand the risk of passing the same disease-causing gene variants on to their offspring.
Dr. Nagiel said those benefits also extend to researchers and biopharmaceutical companies studying potential therapies and treatments. The more these professionals can learn about the genes and variants responsible for IRDs, the easier it is to identify patient populations who might benefit most. In other words, genetic testing can not only name an IRD, but also help connect patients and their families to clinical trials and future treatments.
Emerging therapies are exciting, but more work needs to be done
Treatment options for IRDs have come a long way over the last decade, starting with Luxturna’s FDA approval in 2017.
Dr. Nagiel shared that a lot of the current work researchers are doing is focused on finding therapies that could potentially treat a wider range of genetic abnormalities. The challenge is that there are hundreds of genes and countless variants responsible for IRDs, so creating a separate treatment for each one isn’t practical.
One way scientists may get around this challenge is with a “platform” approach to therapeutics, which emphasizes a standardized, reusable technological framework. For instance, antisense oligonucleotides (ASOs) are pieces of genetic material that can change how a cell processes RNA.
Dr. Nagiel said researchers are using a specific ASO approach called exon skipping to help cells skip specific exons during RNA processing, allowing them to bypass certain disease-causing mutations.3 Early results have been promising, but more work needs to be done.
How clinicians can support patients with IRD
IRD patients and their families often spend years trying to get answers about the symptoms they’re experiencing, and because there are so many different genes involved, tests aren’t always able to provide the answers they’re looking for.
Even so, clinicians can better support these individuals by familiarizing themselves with available genetic testing resources and developing relationships with genetic specialists who can help them manage challenging cases. Similarly, you can keep tabs on clinical trials and emerging therapies that might benefit the patients with IRDs in your care.
Diagnosing and treating IRDs isn’t easy, but Dr. Nagiel closed on a hopeful note. “If we can get to that point where [clinicians] and regulators can all agree that [platform approaches are] safe, then that would be a huge advance because…we could potentially target many genes and not have to reinvent the wheel with each and every one.”
This article was written by Chad Birt based on the recorded conversation between Drs. Singh and Nagiel.
