For the millions of patients with atopic dermatitis (AD), the most common form of the skin condition eczema, life can be a frustrating cycle of scratching, steroid creams and religious moisturizing. In Singapore, over 20 percent of 7-12 year-olds are afflicted with the condition, which can have a serious impact on their life quality by causing severe itching, disrupting sleep and knock-on effects such as the inability to focus in school, mood changes and mental health issues.
Nearly 60 percent of the individuals with AD go on to develop another atopic condition such as allergic rhinitis or food allergy, a phenomenon termed the ‘atopic march.’ This allergic sensitization typically begins with excessive allergen exposure through a leaky skin barrier. With the resulting dry skin and scratching further damaging the skin barrier, it can quickly become a vicious cycle of worsening symptoms.
“If we want to treat AD, we need to break this cycle and address this problem at its source by targeting the molecular basis for the skin barrier defect,” explained Prabha Sampath, a Senior Principal Investigator at A*STAR’s Skin Research Institute of Singapore (SRIS).
When they studied the levels of microRNA (miRNA) in AD patients using a microarray, Sampath and her team found that while miR-335 was present in healthy skin, it was completely absent from the skin of AD patients. Investigating further, they showed that the loss of miR-355 caused the suppression of genes related to epidermal differentiation, ultimately leading to a defective skin barrier.
Looking upstream of miR-355 on the genome, the researchers noticed a large number of histone acetylation sites, suggesting that miR-355 expression could be regulated by histone deacetylating enzymes. To test their hypothesis, they treated cells with Belinostat—a histone deacetylase inhibitor that has been approved as a cancer drug—and found that it restored miR-355 levels as predicted.
“Belinostat was the only one out of a library of drugs that we tested for this purpose; the other drugs did not fulfill our stringent criteria for efficacy and non-toxicity,” Sampath said.
Moving forward, the team is now developing Belinostat into topical treatment for AD. “Our ultimate aim is to provide a safe and effective product that can be used to treat skin barrier defects associated with AD, thereby preventing further disease progression and atopic sensitization,” she added.
The A*STAR-affiliated researchers contributing to this research are from the Skin Research Institute of Singapore (SRIS) and the Institute of Medical Biology (IMB).
