Eyeworld

EW CATARACT 30 February 2016 According to a 2010 World Health Organization (WHO) report, cataracts account for 33% of overall visual impairment but are respon- sible for 51% of blindness in the world. Ninety percent of people with some form of visual impairment live in developing countries, and according to WHO, 80% of visual impairments in the global popula- tion could be prevented or cured. The aim of this research was to find a compound that would main- tain crystallin solubility and even reverse the aggregation of crystallins that had clumped together to form amyloids. The team first established a method for evaluating compounds that could help maintain crystallin solubility. From more than 2,400 compounds, they homed in on a group of 12 related sterols, which they investigated further. Two were identified as being particularly potent for this purpose, and 1 was refined to be more easily distributed to the eye in a topical manner. Then the team proceeded with in vivo and ex vivo experimentation of com- pound 29. Challenges compound 29 will face Richard Lindstrom, MD, adjunct professor emeritus, University of Minnesota, Minneapolis, said he was "intrigued" by the study but also considered it "déjà vu all over again." "There are compounds that have worked in the lab but have failed clinically," Dr. Lindstrom said, noting the challenge of maintain- ing enough of such a compound for a long enough period of time in the human eye in spite of the continuous replacement of aqueous humour. Dr. Lindstrom pointed out that research has been conducted already on glutathione and other antiox- idant drops to reverse or prevent cataracts. Some of these, he said, are on the market in Europe, but the "bottom line is they're a placebo because they don't get into the eye in adequate concentration." Dr. Lindstrom also mentioned that Encore Vision (Fort Worth, Texas) is in clinical trials with its drug EV06, which although it is in- tended to be a topical treatment for presbyopia, could have applications for cataracts as well. "They're attacking presbyopia initially but the natural aging of the lens that occurs … is both the etiol- ogy of cataracts and presbyopia," Dr. Lindstrom said. Addressing this challenge— maintaining enough of the com- pound in the eye for a long enough period of time to be effective—is one Dr. Gestwicki said ViewPoint Therapeutics (San Francisco), the company he helped cofound, is tackling with further research. He also said they'll be evaluat- ing compound 29's toxicity before heading into clinical trials with dogs and rabbits, something he hopes would start within the next year or so. "You need it to be incredibly safe," he said. "The surgery is incred- ibly safe, so there is a very high bar for safety and tolerability of these molecules." Dr. Ravindran thinks that while such an eye drop could be a solution for patients who are unable to get cataract surgery as treatment, it still doesn't address the root of what is causing cataracts in the first place. He would expect surgery to still be the best option for cataract patients hoping for the clearest vision possi- ble, even if a cataract-reversing eye drop were available. "I think we have to look at a solution like this eye drop and the whole socio-economic condition of the people," Dr. Ravindran said. "Even if you delay the problem, you are not removing the cataract-caus- ing agents." Dr. Lindstrom also pointed out that if such drops were developed and deemed effective for human use tomorrow, he thinks even the youngest of ophthalmologists would still be performing a wealth of traditional cataract surgeries with an increasingly aging population. "This is nothing that's going to change the way any of us practice any time soon," Dr. Lindstrom said. EW References 1. Makely LN, et al. Pharmacological chaperone for a-crystallin partially restores transparency in cataract models. Science. 2015 Nov 6;350(6261):674–7. 2. Pascolini D, et al. Global estimates of visual impairment: 2010. Br J Ophthalmol. 2012;96(5):614–618. Editors' note: Dr. Gestwicki has financial interests with ViewPoint Therapeutics. Dr. Lindstrom has financial interests with Encore Vision, Alcon (Fort Worth, Texas), Abbott Medical Optics (Abbott Park, Ill.), and Bausch + Lomb (Bridgewater, N.J.). Dr. Ravindran has no financial interests related to this article. Contact information Gestwicki: Jason.Gestwicki@ucsf.edu Lindstrom: rllindstrom@mneye.com Ravindran: rdr@aravind.org New compound continued from page 29 How to find a treatment for an "undruggable" protein W hen Dr. Gestwicki was researching protein misfolding diseases in his laboratory at the University of Michigan's Life Sciences Institute a decade ago, he admittedly knew very little about cataracts. The challenge the synthetic organic and protein chemist and his lab faced at the time was the blood-brain barrier diseases like Alzheimer's and Parkinson's posed for testing their hypotheses of different interventions. He was later reading about other protein-misfolding diseases, came across cataracts, and found them similar to the ones he had been researching. In contrast though, cataracts in the eye are on the other side of this blood-brain barrier, making it easier for his team to test and prove whether compounds they could create were on the right track. Dr. Gestwicki's lab targeted crystallin, which is considered an "undruggable" protein because it doesn't have enzyme activity, the most traditional target for pharmaceuticals. Thus, Dr. Gestwicki's team first had to establish a new measurement to evaluate if a molecule was influencing crystallin proteins. Leah Makely, PhD, lead author of the study, and Dr. Gestwicki had what he called an "aha moment" and came up with a method —high-throughput differential scanning fluorimetry (HT DSF)—to measure the melting point of the protein. A lower melting point was considered an "indication that the molecule was taking the diseased state and turning it back to something that looked more like the healthy state," he said, because the aggregated proteins would have a higher melting point than healthy crystallins. "We developed this method for finding molecules that could reverse this type of protein aggregation," Dr. Gestwicki said. He explained that this same method could now be used to identify molecules that could be drug targets for other diseases. "I think the implications of this study to the other diseases is at least we have a new hammer in our toolbox, and we can try that hammer against some of the other protein misfolding diseases, and maybe we'll find molecules—not the same molecules for cataracts but maybe we'll find a different molecule—using that approach," Dr. Gestwicki said. EW A visualization of compound 29 Source: Jason Gestwicki, PhD Compound 29

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