AMD grows more common with age, therefore as the overall population ages, the prevalence of this devastating disease is expected to double to 20 million cases during the next 10 years.
Despite its commonness, there are still gaps in scientists’ knowledge about the disease, and treatments target only complications of AMD, not its underlying pathology. The UAB Department of Ophthalmology is pioneering research to fill in those knowledge gaps and help develop more effective treatments.
Understanding the earliest stages of AMD
We believe one key to unlocking the mystery of AMD is understanding the earliest stages of the disease. Currently, scientists do not know what factors cause a transition from a healthy macula to one with AMD. A better understanding of these early stages could provide the foundation for preventing the disease, before it even takes hold.
The Alabama Study on Early Age-Related Maculopathy, known as ALSTAR, aims to identify characteristics that make older adults more susceptible to the earliest emergence of AMD. We are examining many types of factors known to be important for aging-related chronic disease such as genetics, life-style factors such as diet and smoking. Yet a hallmark of ALSTAR is our use of innovative approaches, such as quantitating night vision problems especially as they relate to the microscopic structure of the retina as a measured by high definition optical coherence tomography (OCT). Over 600 older adults in Alabama are enrolled in ALSTAR, and the study will be the first of its kind to examine a multitude of risk factors for early AMD, thus opening the door to better treatments and tools for preventing the disease.
The new generation of clinical imaging promises to bring insights at the cellular level to practicing ophthalmologists. Adaptive optics scanning laser ophthalmoscopy and optical coherence tomography (AO-SLO-OCT) reveals stunning views of individual photoreceptor cells in the living retina. Our experts in high resolution imaging, led by Yuhua Zhang, Ph.D., have brought AO-SLO-OCT into the AMD clinic, where it can reveal the earliest views of cellular damage due to disease as well as cellular repair due to new treatments in trials.
Our scientists have made groundbreaking observations of the microstructure of subretinal drusenoid deposit, a new lesion recently recognized highly associated with progression of this disease. In past decades, ophthalmologists learned about the life cycle and composition of AMD’s signature lesion, drusen, through laboratory techniques like electron microscopy. Only at UAB can we utilize an AO-SLO instrument with uniquely high-resolution and designed with the older patient in mind, enabling ultrastructural analysis in living patients who can be followed over time and after treatments. Because animal models of macular disease have yet to replicate the human condition, our ability to directly study AMD pathology in patients in this manner is significant.
New treatments come from new understanding of eye biology
Christine A. Curcio, Ph.D., a renowned AMD researcher, along with her team, first discovered that a fatty film collects on the flat vessel wall behind the retina, called Bruch’s membrane. This film prevents nutrients from reaching the retina, causing cells to die and leading to the vision loss associated with AMD. As the film develops, it becomes thicker in some locations, which is what creates the visible drusen. “The film is just like an oil spill on the surface of water,” says Dr. Curcio. “And the drusen are like tar balls in the oil spill.”
Through an in-depth natural history and biochemical studies on these deposits, Dr. Curcio and collaborators were able to determine that this oil spill is made up of apolipoprotein B-containing lipoproteins. A famous type of related lipoproteins is LDL (the bad cholesterol).
Further, they were able to conclude that these lipoproteins accumulate throughout adulthood to form the oil spill, and in some ways resemble plaque buildup as seen in the case of atherosclerosis. Dr. Curcio considers both of these factors good news in the development of treatments and cures for AMD.
“This fatty film starts accumulating prior to the occurrence of vision loss, and that gives us an opportunity to do something about it,” she says. “Since we know the molecular basis is similar to that of plaque in atherosclerosis, we can borrow from the extensive research in that area when exploring treatment options for AMD.”
A third key discovery was finding that the components that form this fatty film are actually made within the eye itself as part of a natural process. With this finding, Dr. Curcio and Clyde Guidry, Ph.D., in the UAB Department of Ophthalmology, began collaborating to replicate the fatty film in cell culture. They were successful, therefore creating a novel, reproducible model that scientists can use to test new treatments for AMD.
This is a significant breakthrough, because laboratory animals do not replicate AMD pathology, so previously there had been no way to conduct large-scale studies of AMD treatments. This system has already received attention from major pharmaceutical companies and paves the way for the development of treatments that target the disease’s underlying pathology.
With the help of this cell culture system, unique to UAB, researchers want to take multiple approaches to finding new treatments for AMD, including:
- Just as in an environmental oil spill, the flow of lipids out of retinal cells into drusen can be slowed down (Top Kill), or the lipids already in the oil spill can be removed with drugs that act like skimmers and dispersants.
- Implanted stem cells are currently being developed as an important surgical option for AMD patients. Lipid-cleansing drugs could be deposited in the eye with these cells, refurbishing the surgical bed and providing extra repair and renewal capability.
- Controlling fats by including components of omega-3 fatty acids or other nutrients in the diet may affect how the RPE processes fats, reducing the flow of lipoproteins.
- Knowing the molecular basis of AMD’s oil spill advances the possibly of developing new drug-delivery options based on nanotechnology, or gene therapy.
In order to further accelerate this research, the UAB Department of Ophthalmology is exploring AMD from various angles. Currently the following scientists are working on different lines of AMD research:
The Department of Ophthalmology is pursuing a multi-disciplinary approach to AMD research through collaboration with faculty in other UAB departments.
- Medha Prabhakar Manchekar, Ph.D.
- Xincheng Yao, Ph.D.