The Eye & Ear Foundation closed out April with a webinar entitled, “Age-Related Macular Degeneration and Geographic Atrophy: Advancements in Research and Care.”
The first presenter was Kunal Dansingani, MBBS, MA, FRCOphth, Associate Professor in the Retina and Vitreous Service at the UPMC Eye Center. He described himself as a retina specialist who sees patients with surgical problems as well as medical retina problems. In the non-surgical group, age-related macular degeneration (AMD) accounts for about 40% of the practice.
Age-Related Macular Degeneration
AMD affects 1 in 8 people over the age of 60. Currently 200 million worldwide have the condition. By 2040, it will impact 300 million people worldwide. It is chronic and progressive and is neither curable nor reversible. It involves the disruption of tissue architecture, leading to loss of cells, which results in a loss of function.
AMD, however, is not universal. Not everyone gets it. There are risk factors that increase its incidence. “We like to think there must be a way to slow down or prevent it,” Dr. Dansingani said. “That’s where a lot of research effort is directed.”
The very central part of the retina is the macular. From a vision perspective, this area corresponds to the central part of vision. This is the part of the retina used when you look at or talk to someone and recognize their face. We also use this region when reading. It may be a small part of the retina, but it is disproportionately impactful when something goes wrong, Dr. Dansingani said.
Optical Coherence Tomography
An imaging technique called optical coherence tomography (OCT) captures a 3D image that can be sliced in different directions – usually horizontally – for a cross-sectional image. Almost everyone who comes into the clinic with a macular condition will have OCT. It is high resolution and does not show individual cells in most cases but shows the component layers of the retina.
Disease Patterns
Dr. Dansingani showed some OCT scans to explain disease patterns. For example, patients are often referred to the clinic because they are told they have drusens. These are granular little yellow-white deposits under the next layer beneath the retina. They are basically metabolic products of the retina, accumulations that represent some kind of dysfunction in terms of metabolism. If they are small and few, their presence does not necessarily constitute macular degeneration, but can be a precursor – especially if they come in different sizes and distributions.
Drusens can come and go. They can change and become visually significant. Sometimes they can be associated with early atrophy or cell loss – a loss of pigment epithelium cells. This means this tiny patch of retina is not functioning correctly.
Geographic Atrophy (GA)
Geographic atrophy is when atrophy occurs in contiguous zones and typically get larger over time. They represent a defect in the layer of pigment epithelium. They manifest as blind spots in the patient’s vision. They come in different patterns, which important when looking at different treatments because not all GA is the same.
Neovascularization
A major pattern of disease and vision impairment in macular degeneration is neovascularization – or what people refer to as wet macular degeneration, or the wet complication. The pigment epithelium is a dense meshwork of blood vessels. In wet complications, these blood vessels that are supposed to be confined in the choroid have elevated the pigment epithelium because they have grown and invaded that space. They leak fluid, which gives the disease its name. The good news is there is treatment.
A time-sensitive symptom of macular degeneration is distortion. If left untreated, it can lead to bad outcomes like macular hemorrhage and scar formation. Blood in this space is bad news, Dr. Dansingani said, because it leads to scarring. Normal tissue is replaced with scar tissue, which does not serve any visual function. This leads to a very distorted blind spot in the central vision.
For neovascular/exudative AMD, anti-VEGF injections like Bevacizumab (Avastin), Ranibizumab (Lucentis), Aflibercept (Eylea) can be given monthly. Sometimes when the disease is under control, they can be spread out to every two to three months. Faricimab (Vabysmo) is a newer agent that inhibits VEGF and angiopoietin-2. It stabilizes some of the abnormal blood vessels. However, they are still learning how to best use this; it may not be the best drug to use in early stages.
The two patterns of macular degeneration (GA and neovascularization) are not mutually exclusive; they can occur in the same eye.
Complement System
Treatment for dry macular degeneration has not had any effect, until recently. Now researchers are taking a closer look at the complement system. The body has a system of molecules called a complement system, which can be triggered by certain kinds of infections or foreign bodies. This activates a sequential domino-like effect which culminates in the formulation of something called the membrane attack complex.
It turns out that certain patients who develop macular degeneration have certain genetic variations in their genes that code for these complement components. This has led to the hypothesis that complement cascade activation might be one of the factors causing the demise of cells. Therapeutic intervention targeted at stopping the complement cascade might be a way to treat dry macular degeneration.
Stages of AMD and Opportunities for Therapies
Dr. Dansingani handed the presentation reins over to John Ash, PhD, E. Ronald Salvitti Professor of Ophthalmology Research, Vice Chair and Director of Research. His research focuses on mechanisms of vision loss from inherited retinal degeneration and age-related macular degeneration.
Dr. Ash shared his excitement at moving into the Vision Institute space, which has helped bring the entire Department together. Now that they are all assigned to one space, there have been more conversations with clinicians and scientists than ever before.
Patients still have useful vision in normal, early, and intermediate AMD. Therapies are being developed to prevent progression in the early and intermediate stages. In late GA, Syfovre (Apellis) can be used, along with stem cell replacement, prosthetic augmentation, and optogenetics. Anti-VEGF and other inhibitors of angiogenesis can be used in late wet AMD.
Syfovre’s effectiveness is not clear yet, however.
AMD is an inherited disease and has a total of 62 gene associations. Many targets for the complement cascade came up, which led to the idea that these will be important targets for preventing late-stage disease. The first identified was complement factor H, which contributed to the idea that over-activation is one of the primary causes of disease. A lot of research has jumped onto this.
“We have a lot more work to do, and a lot more pathways, not all involved in complement,” Dr. Ash said. “Many are not. We have to identify what those are and what role they play in developing disease.”
Multiple genes in the complement cascade are associated with AMD. Many of the mutations involved are not in downstream events, but in upstream effectors. Perhaps the new target should be moved and ways to prevent the initial takeover should be focused higher up on the pathway. They are working on ways to regulate the pathway better because completely inhibiting it would affect this very important mechanism of our defense against foreign bacteria, viruses, and tissue damage.
Genetic Risk, Lifestyle, and AMD in Europe
It is possible for patients to inherit not just one gene, but multiple, associated with AMD. It depends on how frequent they are in the population. It is very high in European populations. There is an overlay between behavior and genetic risk. If you have a low genetic risk but very high misbehavior, you can have a 3-5-fold increase in risk. Likewise, if you have a very high genetic risk, but very low risk behavior, you can reduce your risk of developing AMD by the same 3-4-fold. “It is very clear we can affect the genetic risk,” Dr. Ash said.
To lower your risk:
- Avoid high-fat and high-glycemic index diets
- Don’t smoke
- Take AREDS2 supplements
- Moderate alcohol consumption
It is not possible to look at a patient and with 100% accuracy predict they will develop AMD. This is why they do not do genetic testing; it also does not really affect therapy in any way. Maybe one day it will get to that point.
In terms of the effects of smoking and alcohol on AMD risk, there is no difference in risk until mid-to-late 60s.
There is currently a large European study that represents 45,000 people – mostly male, mostly European and Caucasian, which means the data is not highly represented, but does represent a group that is higher risk. They look at medical records, clinical diagnostics associated with risk, and found that high cholesterol – especially high HDL cholesterol – is associated with a higher risk of developing AMD. Risky behavior becomes more prominent with age.
A surprising result is that diabetics have less risk of developing AMD, again confirming the nutritional link. A theory is that metabolism can help protect against disease, but this is a work in progress. “I’m not recommending that people become diabetic to reduce the risk of AMD – not a good idea,” Dr. Ash cautioned.
Understanding Risk Factors to Develop Therapy
In the 62 genes, there are 82 mutations. That, plus being over age 65, and behavior (smoking, alcohol, obesity, high-fat diets), and exposure (microbiome, environmental toxins) can all lead to a vicious cycle of abnormal metabolism, loss of cellular function, increased oxidative damage, cell death loss of vision, and increased local inflammation.
In the lab, Dr. Ash is hoping they can restore metabolism, maintain cellular function, decrease oxidative stress, reduce inflammation, and prevent loss of vision. “We are really focusing on restoring metabolism as a key event that integrates multiple risk factors in preventing disease progression,” he said.
New Therapies Under Development to Prevent Progression to Late-Stage AMD
Drugs: Metformin, 8-OH-DPAT
Proteins: LIF, OSM
Gene Therapies: LIF, Stat3, PGC-1a
Patients taking metformin have seen reduced risk. There is some clinical evidence that some of these drugs that can change metabolism can be protective; more work needs to be done on this. They are also looking at the kinds of stress factors that can be regulated to slow down progression. Patients do not like frequent injections, so developing these into gene therapies that will last longer is one goal.
“We are looking for more gene therapy approaches so that we can have longer useful vision,” Dr. Ash concluded.