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.

ADVERTISEMENT

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.

ADVERTISEMENT

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.

ADVERTISEMENT

About The Author

Nico Ghilardi is an Associate Director and Principal Scientist of Immunology at Genentech.

For the majority of my career, I have focused on investigating the biology of cytokines. Cytokines and their receptors represent excellent targets for pharmacological intervention, not only because they are accessible to protein therapeutics, but also because many of them have very specific biological functions and are often found to be involved in disease pathophysiology. My lab has specifically focused on IL-27, IL-23, and IL-31 over the past few years. In addition, we are interested in defining and pursuing novel small and large molecule targets for therapeutic intervention in immunological diseases.

Most recently, my lab has become interested in the interaction of commensal microbiota with the host immune system, because commensals play a vital role in “educating” the adaptive immune system. This rapidly evolving field is still in its infancy, but we believe that a better understanding of microbiota will lead to novel approaches to target human inflammatory and autoimmune diseases.