The Eye & Ear Foundation’s July 11th webinar, “Next-Generation Therapies to Slow or Halt AMD Vision Loss,” featured presentations by Dr. Jay Chhablani, MD, and Dr. John Ash, PhD. “We really love these webinars because we get to share what’s going on in the Vision Institute to our patients who are interested in what’s up and coming,” Dr. Chhablani said.
Retinal Structure
Macular degeneration affects the central most part of the retina, called the macula. The retina is one of the layers of the eye, but the retina itself has 10 layers. The retina is pretty much an extension of the brain, which has all types of important cellular architecture. Individual cells play a very important role.
AMD is divided into two types: dry and wet. Early and intermediate stages have drusen. Very advanced stages show atrophy. Many times, dry AMD can convert to wet. Patients can have large subretinal bleeding which leads to sudden vision loss.
Wet AMD – Subfoveal CNV
This condition occurs when abnormal blood vessels under the retina form and start leaking or bleeding. Patients will have significant vision loss and need immediate treatment.
How do patients know there are changes in their vision? They will be asked to do Amsla’s Grid, which has vertical and horizontal lines with a dot in the center. Everything looks straight. If they cover an eye and look at it and have a disease involving the macula, they will see some form of distortion.
Early Dry AMD Management
Nutritional support, such as having a healthy diet high in antioxidants, going on the Mediterranean diet, and using AREDS2 eye vitamins, is important. Smoking has a very strong association with AMD, so quitting the habit is essential. UV protection and surveillance – home surveillance, retinal imaging, and period ophthalmic exams – are also key.
“The most important thing is to identify this disease very early,” said Dr. Chhablani, Director of Clinical Research and Vice Chair of Clinical Trials. “Early stage has mostly supportive treatment, as there is no definitive way to stop the disease.”
Advanced Stage AMD Current Drug Treatments
For wet AMD, anti-VEGF therapy is at least two decades old. These injections have a significant benefit, as they not only stop progression but improve vision. They need to be done on a regular basis, however, as the disease can come back once the injections are stopped.
Advanced atropic (dry) AMD means anti-complement therapy. Two monthly injections got approved recently, the first approved treatment for geographic atrophy.
Low Vision Aid/Therapy
Unfortunately, progression cannot be prevented in many patients, so low vision aids are offered, like special lenses, electronic systems, digital aids, and OT training. There are surgeries like an implantable telescope that are not done in the VI because the results are not great. This procedure is done in Europe often.
“We don’t give up; we offer patients options to help them perform routine activities,” Dr. Chhablani said.
AMD Research: Emerging Therapies and Future Directions
Pharmacologic therapies include new drug targets, sustained release delivery systems, neuroprotection, and combination therapies. The newer drugs allow patients to get an injection break for almost 3-4 months.
Regenerative medicine, like stem and cell-based therapies and tissue engineering, is still in the trial stage or on the development side. Lots of research is happening here at the VI.
UPMC is very much leading the way in advanced technologies like an artificial retina and optogenetics. Multiple trials are underway on gene therapy for AMD, with promising results. These therapies are still in an evolving phase. Patients need to be followed for a very long time, and only then will the FDA approve. “But it is a very exciting time for our patients, with certain treatment options coming up that can stop progression or recurrence,” Dr. Chhablani said.
Photobiomodulation was recently approved by the FDA and is available at multiple sites. The VI is yet to offer this because more data and real-life benefits are needed. This has existed for quite some time, particularly in Europe. We will learn more in the coming years.
Gene Therapy: A Lasting Solution?
Viral vector gene therapy utilizes vector-based introduction of a desired gene that uses the native cellulary biomachinery to produce a desired protein, otherwise known as a “biofactory.”
Multiple gene therapies are coming for both dry and wet AMD. “I’m really excited that in the next couple of years, we’ll be able to offer these options for our patients,” said Dr. Chhablani.
Photovoltaic Restoration of Central Vision in Atrophic AMD
A 2-mm wide, 30-mm thick wireless photovoltaic prosthesis (PRIMA) containing 378 pixels helps provide central vision to subjects with geography atrophy. It involves electrical stimulation transmitted to retina nerve cells, which then converts them to action potentials via wireless activation with near-infrared light.
The VI has included a couple of patients in this trial, and the results are looking very promising. There do not seem to be any side effects.
Importance of Early Detection
Dr. Chhablani emphasized the need to identify patients with AMD before the disease progresses. It is very difficult to bring back vision once it is lost, so the goal is to identify these patients before they lose that vision.
Dr. Chhablani’s group has been working on developing AI-based tools to help identify the disease early. They have spun out a commercial entity called NetraMind Innovations. They will be pushing this technology to rural areas, where patients will be encountering their doctor for the first time.
“Can we actually identify the disease early?” Dr. Chhablani asked. “We are almost there.”
Opportunities for Therapy at Different Stages of Disease
Dr. John Ash, E. Ronald Salvitti Chair in Ophthalmology Research and Executive Vice Chair of Research, has been at Pitt for about 2.5 years now. “I’d say it’s probably the most active and vibrant research center in ophthalmology that I’ve ever worked in, so it’s a privilege to work here with such great colleagues,” he said at the start of his presentation.
In early-intermediate stages of AMD, where patients have useful vision, early detection and predictive tools will help develop therapies to prevent progression. With late geographic atrophy, the stage in which most of the blindness occurs, syovre or lzervay, stem cell replacement, prosthetic augmentation, and optogenetics are the potential therapies. In late wet AMD, anti-VEGF and other inhibitors of angiogenesis are used.
“There are very very limited treatment options to prevent progression from early to intermediate and then to late,” Dr. Ash said. “This is an intense area of research for new therapy development.” With a progressive disease, much relies on early detection. The ability to identify who needs intensive therapy is also useful for future clinical trials to help determine/track whether therapies are effective.
One of the reasons why there are no therapies for the early stages is because of clinical trials. Testing new drugs is a horrendous process that takes a lot of patience and many years to figure out if there is a positive result.
Understanding Risk Factors to Develop Therapy
Genetics do not tell the full story, though there are 52 mutations in 32 genes for AMD. Age is part of it – tending to occur in ages 50-65 and people older than 65. Behavior, such as smoking, alcohol, obesity, and high-fat diets, will have adverse effects. Exposure to microbiome and environmental toxins is also a risk factor.
How do these risk factors affect the cells? It’s a vicious cycle of abnormal metabolism leading to loss of cellular function leading to increased oxidative damage to increased local inflammation and then cell death/loss of vision. Treatment options look for things that can restore metabolism, maintain cellular function, decrease oxidative stress and DNA damage.
Metformin
A graduate student in Dr. Ash’s lab, Lei Xu, worked on metformin, a FDA-approved drug used for other purposes. When treated in mice with an inherited mutation that caused photoreceptor death, photoreceptors survived. This drug targets metabolism. The mice could actually see. So if drugs targeting metabolism can be studied to give the retina increased resilience, this will help slow the progression of AMD. Metformin may also help prevent RPE (retinal pigmented epithelia) cells from dying, which also increases resilience.
If there is damage to photoreceptors or RPE, an inflammatory event could lead to activating some immune cells that release proteins that would stimulate. Some responses are beneficial, however. One of them – leukemia inhibitory factor (LIF) is a very potent activator of cell stress responses, a naturally expressed protein that slows and reduces retinal degeneration. It is more effective than metformin, but because it is a protein, it does not last very long. Weekly injections would be needed, which is not a good therapy for multiple years of treatment for a chronic disease. Dr. Ash said they are looking at ways to improve this.
Another grad student who worked with Dr. Ash in the past, Clayton Santiago, worked on drug-regulated LIF gene therapy, packaging it in an AAV vector to deliver to the eye. This way the amount of protein is controlled. In animal models, they found long-term protection of rods and cones. The mice could also see quite well.
In Dr. Ash’s lab and other VI labs, they are developing therapies that would allow them to slow down the progression of early and intermediate AMD, so patients may never reach the late stages. If they have patients they know are going to progress, it is much better to rescue and save their vision before they lose it than try to restore it after the vision is lost. “This is our landscape in the moment in the Department,” Dr. Ash said. “There are other groups here working on other drugs as well, and other gene therapies.”