University of Newcastle respiratory researchers have discovered new factors and a pathway that may drive the onset of steroid resistance in severe asthma, which they hope could lead to a clinical treatment breakthrough.
In the internationally renowned Journal of Allergy and Clinical Immunology, Professor Phil Hansbro and his team – Dr Richard Kim, James Pinkerton and Dr Jay Horvat – implicate a new molecule called microRNA-21 or ‘miR-21’ as the trigger for a complex biological cascade that drives inflammation and the pathogenesis of severe asthma.
“Steroid resistance is the biggest issue in severe asthma and effective treatments are urgently needed,” Professor Hansbro, a member of HMRI’s VIVA program, says.
“People with asthma don’t mount effective immune responses to viruses and bacteria and this makes them more susceptible to infections. These infections then drive steroid resistance and a severe asthma phenotype.”
To explore the mechanism, Prof Hansbro’s team used a world-leading laboratory model to replicate a steroid-resistant asthma attack, induced by both infections and allergens. The aim was to gauge the suspected role of various microRNAs that are known to bind to different genes and fuel inflammation.
“Just before we gave a second allergen dose to induce a severe asthma attack we profiled the overall expression of microRNAs and found that miR-21 was the most highly expressed,” Prof Hansbro says. “We then followed the mechanism pathways.
“One is called PTEN, an anti-inflammatory gene, which is suppressed by miR-21. This then causes an increase in the enzyme PI3 kinase, driving further inflammation, which finally inhibits a molecule known as HDAC2 [Histone deacetylases].
“HDAC2 is really important in responding to steroids in mild to moderate asthma. We’ve shown in our modelling that the pathway works with four different types of bacterial and viral infections in the respiratory tract, so it’s reasonably generalised.”
Prof Hansbro’s team is now aiming to develop a novel therapy to eliminate miR-21 and therefore inhibit the ensuing cascade.
By artificially replicating the PTEN gene fragment, they hope to confuse miR-21 into binding to the dummy rather than actual gene.
“We’ve done it in modelling and shown it works,” Prof Hansbro says. “It suppresses inflammation and severe asthma and restores the responsiveness to steroids.”