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EW RETINA 52 work needed for human clinical trials. In such trials, Dr. Kiser is partic- ularly optimistic about studying the drug cocktail in those with Stargardt disease. "That's very closely related to the model that these drugs have been tested against," he said. By contrast, the concern with age-re- lated macular degeneration is that it is a slow, progressive disease that would require patients to be treated for many years in order to see an effect. "With Stargardt disease, it's a much shorter time course, and we may more easily be able to see if they're effective," Dr. Kiser said. "The best route forward is to test in Stargardt disease as it could be therapeutic in those patients and as a proof of concept for treatment in dry AMD because of some of the similarities between those two diseases." Dr. Kiser hopes practitioners come away from the study with the understanding that systems phar- macology is something investigators should be looking at more often. "It appears to be a powerful approach, and this is something that I think could be applied to other diseases as well," he said. "With our ability now to analyze transcription pro- files, it leads to the opportunity to identify pathways that are dysreg- ulated and then take drugs that we already have in our toolbox and intervene." With a lot of effective medications available these days, combining these could be a way to get therapies to the clinic quicker since many of these molecules are already well-characterized, with known toxicity profiles that are not particularly detrimental to patients, he concluded. EW Reference 1. Chen Y, et al. Synergistically acting agonists and antagonists of G protein-coupled recep- tors prevent photoreceptor cell degeneration. Sci Signal. 2016;9:ra74. Editors' note: Dr. Kiser has no financial interests related to his comments. Contact information Kiser: Pdk7@case.edu by Maxine Lipner EyeWorld Senior Contributing Writer Synergistic effect As part of the study, investigators took a closer look at four out of 20 identified agents—bromocriptine, metoprolol, doxazosin, and tamsu- losin—that might work to protect the retina from light damage. They looked at these individually and then considered two different low- dose combinations. Both of these contained bromocriptine, known for its effect on dopamine receptor signaling, and metoprolol, a beta receptor antagonist. One of the com- binations also contained doxazosin and the other tamsulosin, which are both alpha receptor antagonists, Dr. Kiser explained. "Those drugs were tried indi- vidually at higher doses, and we found with the higher doses they were protective," he said. However, there are concerns about using such amounts in humans due to side ef- fects. While at lower doses such side effects would not be an issue, each medication alone would not have been effective. "However, by giving them in combination, we found that we could get complete protection against the retinal degeneration that occurs when we expose those mice to bright light," Dr. Kiser said, adding that the drugs appear to be working synergistically. He theorizes that the agents are working together at a transcrip- tional level. "The data indicate that these drug combinations are able to normalize the retinal transcriptome more completely than the higher dose monotherapies, and this likely has an impact on protection of the retina from light damage," Dr. Kiser said. Known appeal Dr. Kiser is optimistic about the pos- sibility of using such agents together for retinal protection. "Clinically, what we have here are drugs that are already FDA approved," Dr. Kiser said. "That makes it a lot easier to test these combinations in humans because we already know the safety profile of the drugs well since they've been in the market for a long time." Now the investigators are trying to do the background Chen, PhD, decided to take a closer look at a mouse model in the lab that emulated retinal degenerations, Dr. Kiser explained. "We knew that it was susceptible to light damage, and she started looking into the pathophysiology," he said. "She found that one of the proteins being activated in these mice leading to oxidative stress and retinal degener- ation is called NADPH oxidase, and this is a protein that's activated by calcium." This, in turn, implicated G-protein signaling in the mouse retinal degeneration pathogenesis and put the focus on antagonists to these. "She started out with the logical things to target—G-protein coupled receptors that are activat- ing calcium signaling," Dr. Kiser said. "She tried other ones, too, and found those could work." Combination of FDA- approved drugs studied to stave off retinal damage C ould a combination of already FDA-approved drugs work to prevent macular degeneration, Stargardt disease, and other sight-threatening disorders? A new study indicates that a low-dose cocktail of bromocriptine, metopro- lol, doxazosin, and tamsulosin had a protective effect for photoreceptor cells against bright light, according to Philip Kiser, PharmD, PhD, assistant professor, Case Western University School of Medicine, and research health scientist, Louis Stokes VA Medical Center, Cleveland. 1 The idea for the study originat- ed when one of the investigators, Yu In plain sight February 2017 Research highlight Mouse eyes treated with the drug combination bromocriptine, metoprolol, and tamsulosin were protected from damage, unlike those that were treated with vehicle, as seen in these OCT and SLO images. Source: Philip Kiser, PharmD, PhD

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