Nav: Home

Alcohol abuse drug can be repurposed to treat a blinding disorder

August 04, 2016

New research from University College London, Moorfields Eye Hospital and Duke University School of Medicine has identified a gene that drives scarring, together with a rapidly translatable therapy, for the UK's most common cause of blinding conjunctivitis. The results demonstrate that the drug disulfiram, licensed for the control of alcohol abuse, normalises human and mouse scar making cell (fibroblast) functions and inhibits mouse ocular mucosal (conjunctival) scarring. Fight for Sight, UCL Business, and Moorfields Eye Charity funded the study, which is published in the Journal of Clinical Investigation Insight on 4 August.

Scarring conjunctivitis is a major cause of chronic pain and sight loss. The conjunctiva is the membrane that lines the eyelid and covers the eye. In health, it helps lubricate and protect the eye, but in conditions such as ocular mucous membrane pemphigoid (ocular pemphigoid), severe eye allergy, Stevens-Johnson syndrome, and trachoma inflammation trigger rapid pathological scarring, which often persists after the inflammation has gone destroying the protective functions of the conjunctiva.

Ocular mucous membrane pemphigoid was chosen for current investigations because mucous membrane pemphigoid is a prototypical immune mediated mucosal scarring disorder (that affects other mucosal sites at the orifices as well as the conjunctiva). It is also the most common immune mediated scarring conjunctival disease in the UK. Standard treatment for both mucous membrane pemphigoid and its ocular form is to suppress the immune system. This controls inflammation when it works, but there are unpleasant side effects and it has little effect on scarring. Approximately 1 in 5 people with the ocular form go blind.

In the current study, the research team screened for genetic activity linked to scarring in conjunctival tissue, and in the scar making cells (fibroblasts) grown from this conjunctiva. The aim was to identify potential therapeutic target molecules and provide a test bed for treatment.

Professor John Dart and Professor Julie Daniels, both of NIHR Moorfields Biomedical Research Centre and the UCL Institute of Ophthalmology, were joint research leads, together with Professor David Abraham at UCL Royal Free Campus.

Results show that the aldehyde dehydrogenase 1 (ALDH1) family of enzymes is more active in tissue and fibroblasts from people with ocular mucous membrane pemphigoid compared to controls. ALDH1 is an enzyme that's critical for one step in the process of turning vitamin A into retinoic acid - a key protein in immunity, inflammation and scarring.

Conjunctival scarring like that seen in ocular pemphigoid arises in a mouse model of severe allergic conjunctivitis previously developed by study co-author Dr Daniel Saban's team at Duke University School of Medicine. Following the ALDH1 results in tissue and fibroblasts, these mice were treated daily with eye drops containing disulfiram for 7 days after the induction of immune mediated conjunctivitis.

Disulfiram is a drug that's licensed for treating alcohol abuse. It works by blocking ALDH activity, including ALDH2, which processes alcohol. Treatment reduced eye surface inflammation in the mice and prevented scarring compared to controls. Ocular pemphigoid fibroblasts were treated with disulfiram to test its effect on ALDH inhibition in these human scarring cells. In keeping with the in vivo results, disulfiram treatment of human ocular pemphigoid fibroblasts, significantly inhibited their abnormal behaviour in a range of tests.

Dr Sarah Ahadome at UCL Institute of Ophthalmology is the study's first author. She says: "Our results have demonstrated that inhibiting ALDH1 activity with disulfiram effectively reduces inflammation and prevents scarring in vivo, and significantly reduces the signs of scarring in vitro, in human ocular pemphigoid fibroblasts. It may be that this approach will be more effective at scar prevention when there is active inflammation, but this is an important proof-of-concept that currently untreatable scarring conjunctivitis may respond to eye drops or other topical application of a drug that can be repurposed."

A companion study from Dr Saban's lab at Duke University, in collaboration with Dr Virginia Calder's lab at the UCL Institute of Ophthalmology, is being published at the same time. Professor Dart commented on results from both studies: "Collectively there is evidence from our data, and from that of Dr Saban's team, that aldehyde dehydrogenase has critical roles in inflammation and conjunctival fibrosis, and is produced by the dendritic cells of the immune system and by fibroblasts. We suggest that progressive scarring in ocular pemphigoid results from fibroblast self-regulation, mediated by ALDH, through its metabolite retinoic acid (Vitamin A). These findings suggest that the repurposing of disulfiram, for the topical treatment of mucosal scarring in ocular pemphigoid and similar disorders such as severe eye allergy, may result in effective anti-scarring therapy and provide justification for a randomised controlled trial of disulfiram therapy for scarring in OMMP"

Fight for Sight's Director of Research, Dr Dolores M Conroy said: "This is very important work given the devastating impact of progressive scarring on the eye and other organs. There is currently just one licensed drug for fibrosis and that is for lung disease. Mucous membrane pemphigoid affects the eye in 7 in 10 people with the condition, with 1 in 5 going blind. The potential for disulfiram 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.

Professor Phil Luthert, Director of the UCL Institute of Ophthalmology stated:"Scarring remains a major problem in eye disease, and in many other conditions, and uncontrolled conjunctival fibrosis is terrible to live with. This breakthrough offers new hope and is a great example of how discovery science can come together with smart repurposing of existing drugs to reach a solution for patients."
-end-


University College London

Related Immune System Articles:

The immune system may explain skepticism towards immigrants
There is a strong correlation between our fear of infection and our skepticism towards immigrants.
New insights on how pathogens escape the immune system
The bacterium Salmonella enterica causes gastroenteritis in humans and is one of the leading causes of food-borne infectious diseases.
Understanding how HIV evades the immune system
Monash University (Australia) and Cardiff University (UK) researchers have come a step further in understanding how the human immunodeficiency virus (HIV) evades the immune system.
Carbs during workouts help immune system recovery
Eating carbohydrates during intense exercise helps to minimise exercise-induced immune disturbances and can aid the body's recovery, QUT research has found.
A new model for activation of the immune system
By studying a large protein (the C1 protein) with X-rays and electron microscopy, researchers from Aarhus University in Denmark have established a new model for how an important part of the innate immune system is activated.
Guards of the human immune system unraveled
Dendritic cells represent an important component of the immune system: they recognize and engulf invaders, which subsequently triggers a pathogen-specific immune response.
How our immune system targets TB
Researchers have seen, for the very first time, how the human immune system recognizes tuberculosis (TB).
How a fungus inhibits the immune system of plants
A newly discovered protein from a fungus is able to suppress the innate immune system of plants.
A new view of the immune system
Pathogen epitopes are fragments of bacterial or viral proteins. Nearly a third of all existing human epitopes consist of two different fragments.
TB tricks the body's immune system to allow it to spread
Tuberculosis tricks the immune system into attacking the body's lung tissue so the bacteria are allowed to spread to other people, new research from the University of Southampton suggests.

Related Immune System Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#530 Why Aren't We Dead Yet?
We only notice our immune systems when they aren't working properly, or when they're under attack. How does our immune system understand what bits of us are us, and what bits are invading germs and viruses? How different are human immune systems from the immune systems of other creatures? And is the immune system so often the target of sketchy medical advice? Those questions and more, this week in our conversation with author Idan Ben-Barak about his book "Why Aren't We Dead Yet?: The Survivor’s Guide to the Immune System".