November 2015




Following a novel AMD trail

by Maxine Lipner EyeWorld Senior Contributing Writer


New pathway linked to vision loss discovered

While the anti-VEGF pathway has helped to make great strides in the treatment of age-related macular degeneration (AMD), investigators have now identified a new pathway that they hope may stave off the formation of atypical blood vessels, according to Rajendra S. Apte, MD, PhD, Paul A. Cibis distinguished professor of ophthalmology, and professor of developmental biology and medicine, Washington University School of Medicine, St. Louis. In a study published in Nature Communications, investigators highlighted what this pathway has to offer and how this may enable practitioners to halt blood vessel formation even before it begins.

There are many lines of evidence weve had over the years suggesting that the immune system plays a role, Dr. Apte said, adding that he previously found that the interleukin-10 (IL-10) cell-signaling molecule was involved in the blood vessel formation associated with wet macular degeneration. In this latest set of studies, investigators tried to identify what was going on inside of cells that was making them dysfunctional, he explained. Dr. Apte had also previously determined that IL-10 levels increase in the eye prior to vision loss, as well as immune cell macrophages.

Spotlighting the STAT3 pathway

To get a better idea of what might be going on, investigators decided to take a closer look. We looked at two big signaling pathways that we had previously identified as being important, and IL-10 was one of them that changed with age, he said. Investigators then looked at downstream signaling pathways to determine just what got activated in the macrophages, and they were able to identify a protein called STAT3 that appeared to play a pivotal role in causing immune cells to become abnormal, ultimately leading to the formation of harmful blood vessels. We showed that there was a hyperactivation of this one pathway (in older cells) and that the negative feedback loop was also impaired, Dr. Apte said. Whats interesting about this STAT3 pathway is that clinical trials for actual drugs to treat non-ocular conditions have already taken place. Whats nice is we have drugs that can directly target STAT3, he said, adding that the idea would be to potentially use such drugs, or ones like them, in high-risk patients to slow the development of abnormalities. We know from AREDS [Age-Related Eye Disease Study] that the risk, even a 5-year risk, for progression to advanced disease is almost 45%, Dr. Apte said. We can now envision therapeutics that would potentially slow disease progression in this high-risk population.

New treatment possibilities

This new pathway is a VEGF-independent. We cant treat these people with anti-VEGF, Dr. Apte said. They dont actually have wet disease yet. The beauty is that since this is a different pathway, any treatment emerging here might be able to be used in conjunction with anti-VEGF. We have a new avenue that could be synergistic to what were doing, where we could either slow or prevent disease progression, he said. Whats more, there are multiple points in the pathway where it could be possible to intervene. Laboratories, including Dr. Aptes, have previously shown that early in the natural history of macular degeneration, patients develop highly lipid-rich deposits, with cholesterol esters in this drusen underneath the retina, he explained. This usually precedes the advanced stageseither the advanced dry stage called geographic atrophy or the advanced wet stage where we get choroidal neovascularization, Dr. Apte said. However, because the eye offers unique access for treatments, with the new pathway available it might be possible to head this off. The anti-VEGF field has taught us that we can deliver things locally in the eye with lower risks, Dr. Apte said. We could change the capacity of the eye to handle cholesterol. In addition, either by targeting this new pathway or some that others previously identified, clinicians could change the function of these cells; it has already been shown that even though cells in older individuals prone to macular degeneration are dysfunctional, they can be reprogrammed to make them work better. Dr. Apte hopes practitioners take away the understanding that although anti-VEGF drugs have made a real difference in treating advanced stages of disease, these are not a cure. However, he envisions in the next 510 years that in addition to developing a better understanding of AMD, a new set of drugs will emerge that will make a difference in the early stages of the disease as well. It will be like what we do with glaucomawe treat it early before nerve damage because we cant do anything afterward, Dr. Apte said, adding that this will lead to micro- RNA, gene therapy, and immune system approaches for preventing or treating drusen formation. These pharmacotherapeutic approaches will allow us to expand options to people, anticipating what will happen 1015 years down the road, he said. This is particularly compelling in light of longer lifespans where a 75-year-old with AMD can be expected to live for some time. If we can prevent complications, the implications for quality of life are very important, Dr. Apte concluded.

Editors note: Dr. Apte has no financial interests related to this article.

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