Lung–Restricted Inhibition of Janus Kinase 1 Is Effective in Rodent Models of Asthma

Abstract

Multiple type 2 cytokines, including interleukin-4, interleukin-5, interleukin-9, interleukin-13, and thymic stromal lymphopoietin, drive the pathophysiology of an important subset of asthma. These and other cytokines, such as interleukin-6 and type I and type II interferons, depend on Janus kinase 1 (JAK1) for signal transduction. iJak-381 is a synthesized, small, and inhalable molecule that was specifically designed for lung-restricted JAK1 inhibition. The purpose of this study was to conduct preclinical studies to test whether local inhibition of JAK1 can inhibit allergic inflammation in the lungs.The study tested iJak-381 in mice and guinea pigs. Guinea pigs are an ideal species to study lung inflammation because their lung anatomy is similar to humans, and they mount a robust response to inhaled challenges.The authors developed a dry powder inhalation system for iJak-381 and tested its ability to suppress inhaled ovalbumin-induced pulmonary inflammation and airway hyperresponsiveness in murine and guinea pig models.iJak-381 suppressed signal transducer and activator of transcription 6 activation by interleukin-13. iJak381 also suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models. Using human allergens (Aspergillus, Alternaria, and house dust mite Dermatophagoides farinae), iJak-381 had a strong suppressive effect on neutrophilic inflammation compared with systemic corticosteroids. Lastly, iJak-381 reduced lung pathology without inhibiting systemic JAK1 activity.The authors concluded that lung-restricted inhibition of JAK1 suppressed asthma-related lung inflammation in 2 rodent models without systemic JAK inhibition. Because iJak-381 also suppressed neutrophilic inflammation in the lungs, the authors suggest that a combination of inhaled JAK1 inhibition with corticosteroid administration may be an efficacious approach to asthma treatment.This study highlights the importance of JAK1 signaling in asthma pathogenesis and suggests a therapeutic benefit to lung-restricted JAK1 inhibition. JAK1 inhibition may improve lung function by inhibiting both type 2 cytokine signaling and antigen-driven eosinophilic and neutrophilic inflammation in the lungs. More importantly, the inhaled route may provide clinical relief without systemic side effects. These promising preclinical findings suggest that clinical studies should be pursued to test iJak-381 efficacy and safety in asthma.