An international research team including scientists at the University of Texas Medical Branch at Galveston (UTMB) and the Galveston-based spinoff Neurobiotex, Inc. has found high levels of zinc in deposits in the eye that are an indication of age-related macular degeneration (AMD) – the leading cause of blindness in the elderly in the developed world.
The finding, published this month in the journal Experimental Eye Research, contributes to a better understanding of AMD and could facilitate the development of effective treatments, said UTMB ophthalmologist Erik van Kuijk, senior author of the study.
AMD is a form of macular disease that affects the eye’s central retina and afflicts millions of people (30 percent of them over 75 years old) in the United States alone. It is associated with defects of retinal pigment epithelial cells (RPE), the failure of which leads to progressive loss of vision. Despite the potentially devastating impact on patients’ quality of life, no successful therapy to stop or reverse the progression of AMD is available in the majority of cases.
An early sign and a presumed trigger of the eye disease is the formation of microscopic plaques, called “drusen,” in the eye. Exactly what these plaque-like drusen do and why they form is not yet fully understood, the researchers noted. “We have discovered that the drusen in the eyes of those with AMD have very high levels of zinc,” said van Kuijk, associate professor in the UTMB Department of Ophthalmology and Visual Sciences.
Zinc previously had been shown to contribute to the formation of brain plaques in patients with Alzheimer’s disease, so van Kuijk said it was logical for him and his colleagues to test the idea that zinc might also contribute to the formation of the plaque-like drusen in the eye. He said they did so using a reagent called ZP-1 that was developed by Dr. Christopher Frederickson at Neurobiotex, Inc. in Galveston. Frederickson suggested that AMD can be considered “the Alzheimer’s disease of the eye,” in that both disorders involve the aggregation of misfolded amyloid proteins and metals like zinc and copper into microscopic clumps called plaques.
“What is particularly important is that within the zinc we found a small pool – about 5 to 10 percent – of what is known as ‘free’ or ‘loosely bound’ zinc,” van Kuijk explained. “Generally, zinc is essential to keeping a molecule’s shape, but mobilized zinc can cause lots of problems. However, since it is a small proportion of the overall zinc pool, it’s straightforward to target it. That’s what researchers are beginning to do with Alzheimer’s disease by developing methodologies and drugs that can capture this mobilized zinc and see if doing that slows down the degenerative process. This study shows that we could now potentially take a similar route for AMD treatment.”
The researchers looked at eyes procured by the Montana Eye Bank from deceased patients with AMD that contained several large sub-RPE deposits and compared them to postmortem eyes from a similar age group that had no known eye disease and no deposits in the macula. They analyzed these using zinc-sensing molecules like ZP-1, which glow when they bind with zinc. These “glowing molecules” bind only to the free or loosely bound zinc, which is particularly crucial in causing disease.
Although total blindness almost never occurs as a result of AMD, a central portion of vision is lost, van Kuijk noted. This means that the condition can cause serious problems with reading, recognizing people, seeing small objects and driving. The disease is more common in women than in men. Common risk factors are family history and smoking. There are two forms of AMD – dry and wet. Dry AMD means visual cells simply stop functioning, whereas wet AMD is linked to new vessel growth and is the more aggressive form of the disease. Currently there is no treatment for dry AMD, but there has been considerable progress in treating wet AMD, including use of new drugs like Avastin and Lucentis that stop new vessel growth. However, these are only suitable for patients with advanced disease, their effects are often temporary, and they carry the risk of adverse reactions.
“The pioneering work by Dr. van Kuijk and his colleagues is an important development in our understanding of AMD” said Dr Michael Boulton, director of the new Macular Degeneration Center at UTMB. “The possibility of targeting zinc to stop or reverse drusen growth is important because doing so has the potential to arrest the progression of AMD early, before irreversible damage to the retinal cells occurs.”
“A treatment for AMD is desperately needed as the disease affects up to 7 million Americans,” Boulton continued. “This equates to 2,000 AMD sufferers here on Galveston Island.”