Treating Asthma With An Inhalable JAK1 Inhibitor In Preclinical Models
Asthma is the result of a complex and dysregulated immune response in which the bronchial airways become inflamed and constricted. This lead to chest tightness, wheezing, and difficulty breathing. In many cases, these symptoms can be minor and temporary, and they respond well to available medicines, including inhaled corticosteroids, which work by reducing inflammation in the airways, and long-acting beta-agonists, which relax the smooth muscle that lines the airways. However, some of the most severely ill asthma patients do not derive sufficient benefit from these drugs, which is why my team and I are working toward new treatment approaches that target the immunomodulatory pathways that underlie the disease.
A significant subset of asthma cases are driven by the activity of a class of immune signaling proteins called cytokines, specifically interleukin-13 (IL-13), IL-4, IL-5, IL-9, and thymic stromal lymphopoietin (TSLP). Each of these cytokines is responsible for different aspects of asthma pathology, such as smooth muscle contraction, mucus release, and the attraction of inflammatory cells to the bronchial tissue.
IL-4, IL-13, IL-9, and IL-6 all work by turning on a molecular switch inside the cells they act on, a protein tyrosine kinase called Janus kinase 1 (JAK1). Thus, by targeting JAK1, one can suppress the actions of all these cytokines simultaneously. Indeed, preclinical studies have shown that systemic administration of JAK1 inhibitors may be effective, but JAK1 is also associated with adverse side effects that would be unacceptable for long-term therapy in asthma. One way to bypass these problems is to confine JAK1 inhibition to the lungs through the use of an inhalable JAK1 inhibitor.
In a study we recently published in Science Translational Medicine, we described a JAK1 inhibitor with radically different physicochemical properties compared to a traditional orally administered compound. These properties make it ideal for inhaled administration, as they limit exposure of the medicine to the lung but result in rapid clearance elsewhere in the body.
Using this re-designed JAK1 inhibitor, which we call iJAK-381, we showed that local and selective JAK1 inhibition in the lung demonstrated a therapeutic effect in three preclinical asthma models. Specifically, in guinea pigs, whose lung anatomy is more similar to humans compared with mice, iJAK-381 dose-dependently reversed lung pathology as measured by reduction in pulmonary inflammatory cell influx and reduced expression of IL-13-dependent genes. Importantly, we were able to conclusively demonstrate that the activity of iJAK-381 was restricted to the lungs. Thus, lung-restricted JAK1 inhibition is sufficient to inhibit disease in these pre-clinical models.
We’re excited and encouraged by these early results, as they provide some of the first evidence that lung-restricted JAK1 inhibition is sufficient to suppress asthma-related inflammation.
These findings are described in the article entitled Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma, recently published in the journal Science Translational Medicine.