Research ArticleAsthma

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma

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Science Translational Medicine  21 Nov 2018:
Vol. 10, Issue 468, eaao2151
DOI: 10.1126/scitranslmed.aao2151

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Janus goes local in asthma

In asthma, swelling of the airways and increased mucus production cause breathing difficulties that can be life threatening. Although current treatments are effective in most cases, alternative strategies are needed for patients who do not respond to available drugs. Oral administration of Janus kinase 1 (JAK1) inhibitors has been shown to be effective in a mouse model of asthma; however, systemic side effects preclude their use in patients. Now, Dengler et al. have developed an inhalable JAK1 inhibitor specifically targeting JAK1 in the lung. The inhibitor exerted therapeutic effects in multiple asthma models in rodents. The results suggest that local JAK1 inhibition might be sufficient for treating asthma.

Abstract

Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, we hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, we synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Our data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.

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