ADVERTISEMENT

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.

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.

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.

ADVERTISEMENT

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.

Comments

READ THIS NEXT

Chronic Liver Disease Mortality Rates And Geographic Variability In The US

Chronic liver disease (CLD) is a leading cause of death for all Americans. Notably, it is the fourth leading cause […]

Cigarillo Smoking In Canada

Cigarillos, also known as “little cigars,” are the smallest type of cigars and can have added flavors to appease a […]

On The Shoulders Of Giants, Part 1: Henry K. Beecher And The Placebo Effect

When Robert Merton (1910 – 2003) dissected the allegory that we all are “standing on the shoulders of giants” — […]

Coal Pros And Cons

Coal pros and cons can be broken down into relatively cheap, widely available, and low capital investment for coal pros […]

Exploring How Environmental Dynamics Shaped Modern Iraq

Modern Iraq is a relatively dry country faced with mounting water challenges. Ancient Southern Iraq, commonly referred to as Southern […]

Where Are Chromosomes Located In A Cell?

The chromosomes are located in the nucleus of the cell. Both plant cells and animal cells have chromosomes within their […]

“Ambidextrous” Tri-Peptides And Potential Biological Applications

When it comes to the choice “left or right,” nature likes to stick to one. For instance, proteins are all […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?