Eyeworld

EW NEWS & OPINION 28 December 2016 as an effective treatment is very exciting, particularly as we know that it may be closer to the clinic than a drug developed from scratch, and especially if it can also find an application in trachoma, which affects 40 million people around the globe." EW References 1. Chang JH, et al. Ocular cicatricial pemphi- goid: manifestations and management. Curr Allergy Astham Rep. 2005;5:333–8. 2. Ahadome SD, et al. Aldehyde dehydroge- nase inhibition blocks mucosal fibrosis in human and mouse ocular scarring. JCI Insight. 2016;1:e87001. Editors' note: Dr. Dart has no financial interests related to his comments. Contact information Dart: j.dart@ucl.ac.uk inhibition, particularly if it can be achieved by local application to affected tissues, an attractive therapeutic target. … The evidence presented suggests that the repur- posing of disulfiram, for the topical treatment of conjunctival scarring in OMMP, may result in an effective topical antifibrotic therapy and pro- vides justification for a randomized controlled trial of disulfiram therapy for scarring in OMMP," the study authors concluded. Clinical applications At this point, Dr. Dart said his team is working on grants that would al- low them to develop disulfiram into an eye drop and conduct research to make sure that a topical preparation of the drug would be stable. "It works in the lab, but we haven't established whether if you dissolve disulfiram, it is stable in solution for 3 or 4 months, which is the minimum you would want for an eye drop," Dr. Dart said. Dr. Dart thinks the disulfiram could be used for other diseases where scarring is an issue as well. The research team is planning to conduct tests on fibroblasts from Stevens-Johnson syndrome patients, trachoma patients, and scleroderma patients. As of right now, Dr. Dart said he is confident enough in disulfiram's ability to prevent scarring for OMMP patients that if someone came in with severe indications of the disease, suggesting they could scar very quickly, he would use the drug orally, as it is currently formulated. "You'd expect it to work orally," Dr. Dart said. "It's taken in large dos- es. The reason we don't want to use it orally is it has a lot of side effects and therefore is contraindicated for some patients. All I have to do is go to our Drugs and Therapeutics Com- mittee and put in an application for an unlicensed use of a licensed drug," Dr. Dart said. The negative side effects that can occur if taken orally with any amount of alcohol in the system is why a topical preparation, if found effective in vivo with humans, would be preferred. "This is very important work given the devastating impact of progressive scarring on the eye and other organs," Dolores Conroy, PhD, director of research, Fight for Sight, London, said in a press release statement. "There is currently just one licensed drug for fibrosis and that is for lung disease. Mucous membrane pemphigoid affects the eye in seven in 10 people with the condition, with one in five going blind. The potential for disulfiram model for pemphigoid, and al- though it isn't an autoimmune mod- el, our hypothesis is that it isn't the immunity that causes the problem, it's the inflammation," Dr. Dart said. Dr. Dart said work done by Dr. Saban showed that the inception of inflammation in the mouse model was in the dendritic cells, which are involved in the immune response but were not previously thought to be involved in fibroblast activity. "Dr. Saban showed in the mouse—it could be different in humans—that dendritic cells switch on the fibroblasts. What happens in the fibroblasts is that they autoreg- ulate by producing ALDH. … Once it switches on, it doesn't switch off, which is why these cells continue to behave abnormally," Dr. Dart said. "There is something funny about these scar cells," he con- tinued. "We took fibroblasts out, grew them in the laboratory … and showed they continued to behave abnormally. We knew in patients that even when the inflammation has been controlled, half of the patients continue to scar. What we hypothesize is that our finding has demonstrated why that is: Once the fibroblasts get switched on, they overproduce ALDH and [thus] retinoic acid, and that drives them down the pro-fibrotic, scar tissue pathway." Inhibiting ALDH with disulfi- ram, applied topically in the mouse model, was found to reduce and pre- vent scarring in vivo and in human OMMP cells in vitro. "Collectively, there is evidence, including that from our data, that ALDH has critical roles in inflam- mation and conjunctival fibrosis and is produced by [dendritic cells] and fibroblasts. This makes ALDH Drug continued from page 27 Key points • The mechanism for scarring and a treatment for scarring in ocular mucous membrane pemphigoid cases were previously unknown. • Researchers found evidence that fibroblast cells are switched on in these patients leading them to overproduce aldehyde dehydrogenase and its metabolite, retinoic acid, which perpetuates a pro-fibrotic, scarring pathway. • Inhibiting aldehyde dehydrogenase, with the drug disulfiram, was found to return fibroblast cells to a normal state and prevent further scarring. • Further research is looking at a topical preparation of this drug that could be used in OMMP and in other scarring diseases such as trachoma.

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