Researchers Identify Possible Reason LTA4H Inhibitors Often Fail in Asthma Trials

Leftover fragments of the extracellular matrix may play an important role in airway remodeling in patients with asthma, according to a new study that points the way to potential new research avenues.

For the study, investigators looked at the enzyme leukotriene A4 hydrolase (LTA4H), which has been an intriguing but frustrating target for drug developers looking for new asthma therapies.

“Classically, the enzyme LTA4H is recognized for its capacity to generate pro-inflammatory lipid mediator LTB4 [leukotriene B4],” explained corresponding author Robert Snelgrove, PhD, of Imperial College London in an interview with MD Magazine®. “LTB4 is implicated in the pathology of an array of chronic diseases, including asthma, and has thus represented an attractive therapeutic target for the pharmaceutical sector.”

When drug makers developed LTA4H inhibitors, however, they frequently found the drugs failed to have the desired effect, even though they succeeded in reducing LTB4 levels.

In 2010, Snelgrove and colleagues published research on LTA4H that showed it also has an anti-inflammatory role, carried out by degrading matrikine Pro-Gly-Pro (PGP). PGP is part of the extracellular matrix, the non-cell tissue parts that surround and support cells. In patients with chronic lung disease, that LTA4H’s degradation pathway is impaired, leading to the buildup of PGP.

“Given the interest in LTA4H in the context of asthma, we thought it would be interesting to ascertain the significance of the dual roles of the enzyme in the pathology of the disease,” said Snelgrove.

Using a mouse model of allergic asthma, Snelgrove and colleagues showed that although a reduction of LTB4 reduced inflammation and airway hyperresponsiveness (AHR), the global loss of LTA4H still exacerbated AHR. They wrote that the uptick in airway sensitivity was due to PGP’s ability to promote airway epithelial remodeling.

The team went on to show that AcPGP, a structural relative of PGP, sparked mucus production and airway remodeling when introduced into human bronchial cells in laboratory cultures. Sputum samples from 50 patients with moderate and severe asthma also revealed elevated levels of AcPGP.

“We had no real expectations going into the study and were surprised by the novel role for PGP in driving pathological airway remodeling that we uncovered in our mouse model of allergic airways disease,” Snelgrove explained. “In essence, we went where the data took us.”

Indeed, the data could next take investigators down new treatment pathways; however, Snelgrove cautioned that most of the work in the study is based on mouse models, and so, while the breakthroughs could be significant, they need to be replicated in humans.

“It is interesting that we have shown that PGP is elevated in patients with severe asthma, but this needs to be validated in further cohorts of patients and correlated with pathological changes in their airway epithelium and loss of lung function,” he concluded. “Such studies would be necessary to ascertain whether PGP may be used as a biomarker for severe asthma and whether it represents a viable therapeutic target to ameliorate disease.”

If it were proven a viable target, Snelgrove said it is feasible that drugs could be developed to target PGP itself, the enzymes that generate it, or the receptors it binds to.

Furthermore, he advised that investigators would also need to look at PGP levels in patients who have been given LTA4H inhibitors in order to see if the scenario is similar to that suggested by the mouse models. If so, according to Snelgrove, it might be possible to develop a compound or a combination therapy that would diminish LTB4 while still allowing for the degradation of PGP.

The study, “An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness,” is published in Science Translational Medicine.