Treatment of Experimental Asthma by Lung Restricted Inhibition of Jak1

Abstract

Abstract Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as IL-4 and IL-13 that are dependent on Jak1 for signal transduction. Because many of the asthma-related effects of these cytokines are manifested in the lung, we reasoned that combined targeting of these cytokines by means of an inhaled Jak1 inhibitor with lung restricted exposure may confer therapeutic benefit. In order to test this, we synthesized iJak-381, a novel, inhalable small molecule specifically designed for local Jak1 inhibition in the lung and tested dry powder inhaled delivery of iJak-381 in preclinical PK and efficacy studies. iJak-381 suppressed OVA induced lung inflammation and improved allergen induced airway hyper-responsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect than a systemic corticosteroid on neutrophilic inflammation. While iJak-381 strongly inhibited lung pathology, it did not affect systemic Jak1 activity. Our data suggests that local inhibition of Jak1 in the lung might be effective for treating asthma in the clinic.