Matrikines give hint to new asthma meds

The results http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aaq0693 of a British-Spanish-Polish research team headed by Dhiren Patel (Manchester) offers an explanation for the clinical failure and optimization of J&J’s LTA₄H inhibitor JNJ-40929837. JNJ-40929837 was assessed in a human bronchial allergen challenge model of asthma, but despite demonstrating clear target engagement and reducing the proinflammatory compound LTB₄, this drug failed to show any clinical benefit over placebo.

In mice leukotriene A4 hydrolase, a well-known modulator of inflammation, degraded ECM compounds including the matrikine PGP (Pro-Gly-Pro), which has also been found in the lungs of humans suffering from asthma and COPD. When Patel et al inactivated the enzyme in a house dust mite model of asthma, inflammation got weaker because proinflammatory LTB₄ couldn’t be formed in absence of LTA₄H while PGP accumulated  and boosted airway sensivity and ECM remodeling in the lungs.

Furthermore, a structural relative of PGP named AcPGP enhanced mucus production and induced airway remodeling when administered to human bronchial cells in culture. The researchers examined sputum samples from two patient groups (50 patients total) with either moderate or severe asthma and found they harbored elevated AcPGP levels compared to controls. They conclude that remodeling can even develop independently of the inflammation  and thus a more targeted approach towards LTA4H modulation is needed.