Coughing Ourselves to Death

By short-circuiting the innate immune response, a new drug in development may help people with severe asthma and COPD to live longer and healthier lives. It is based on decades of research, at The University of Texas Medical Branch at Galveston, into the genomic pathway that leads to damage to the airways.

By Daniel Oppenheimer          August 7, 2017

 

For 20 years, Allan Brasier and his team in Galveston have been mapping, in extraordinary genomic detail, what happens when people with vulnerable respiratory systems get common viruses.

Their goal is to understand, and ultimately help prevent, a damaging internal process known as “airway remodeling.” This process, which is a side effect of our own immune system’s efforts to fight viruses, often begins as a simple and beneficial defense. The problem arises when it goes on too long and too intensively. The airways can thicken and scar. Over time, as someone with a chronic respiratory problem is infected with common viruses, the remodeling continues. The airways grow stiffer and stiffer, and respiratory function deteriorates, in some cases severely.

This can occur in very young infants who contract RSV, in smokers who develop Chronic Obstructive Pulmonary Disease (COPD), in people who suffer from multiple episodes of acute asthma, and in people with cystic fibrosis.

The pathway Brasier and his colleagues have elaborated is both groundbreaking as basic science, and an extraordinary resource for potential treatment. It illuminates the domino chain of genomic transcription and expression, involving thousands of genes and other molecules, from the moment a virus invades a body to the eventual petering out of the immune response and the return to homeostasis. It has enabled Brasier and others to develop ways to potentially sabotage the system and to reduce, perhaps dramatically, the long term damage done by viral infections.

“You have to understand the mechanism,” says Brasier, Professor of Endocrinology and Director of the Sealy Center for Molecular Medicine. “If you don’t understand the mechanism, you have no way of coming up with any therapeutic. There is just a lot of detailed, grinding biochemistry that needs to be done before you have therapeutic potential.”

The Double Edged Sword of the Innate Immune System

The key thing to understand, says Brasier, is that when it comes to airway remodeling, it’s not the virus itself that’s doing most of the damage. It’s our own innate immune response to viruses.

When vulnerable lungs and airways encounter viruses, the process of fighting off the infection, rather than the virus itself, can produce permanent stiffening and scarring. The response can also epigenetically reprogram how the system responds to future infections. This then exacerbates the scarring and causes further deterioration of respiratory function.

“There are currently no therapies that treat this airway remodeling,” says Brasier. “Over time the airways get stiffer and stiffer, and it can dramatically reduce quality of life, to the point where people can’t exercise or even walk.”

Whenever any of us is infected by a virus, explains Brasier, two distinct immune responses are triggered. The more precise and ultimately more powerful of these systems is the adaptive immune system, but it’s slow. It can take up to a week to fully kick in. When it does finally take to the viral battlefield, its soldiers are specific, targeted antibodies to a given virus. The antibodies don’t just clear out the infection from our body. They stick around, in case that specific virus returns.

This adaptive response is why most of us only get chicken pox once. It’s why the vaccines we get as children can prevent us from ever getting infected by viruses like measles, mumps, and bacteria like diphtheria and pertussis (whooping cough). They are cleverly designed to mimic dangerous viruses and bacteria, thus persuading the adaptive immune system to produce antibodies to those viruses without infecting us with the actual viruses.

The innate immune response, by contrast, is a fire alarm. Its sprinklers go off everywhere, even in the rooms where there’s no fire, and then continue sprinkling for long after the fire is extinguished. It’s a much faster but less precise defense. It triggers immediate responses like inflammation, clotting, and fever. It also sends signals to the adaptive immune system to begin developing its more targeted response. This innate system is essential to keeping at bay all sorts of dangers, all the time. It can do life-saving work when confronting dangerous infections, slowing down replication and containing the damage viruses do until the adaptive immune system is ready to go to work. But it can also hurt us.

Precisely those tools the innate immune system deploys to fight viruses, like inflammation, can fight our bodies as well. In the long run of human evolution, this has been an adaptive trade-off worth making. Most of the time, in our individual lives, it is a net benefit. We clear the virus, and suffer no permanent harm. In some instances, however, the collateral damage done by the innate immune response can exceed whatever good it does in fighting off a virus. It’s this dynamic, says Brasier, that seems to be occurring in certain people with vulnerable respiratory systems.

“We discovered,” says Brasier, “that there is an oxidative stress that happens when the virus replicates in cells. That oxidative stress sets off an intercellular signaling pathway, which leads to a modification of a protein complex called NF-kappaB [en-ef-kappa-bee]. That in turn controls the expression of thousands of genes in the cells of these airways, including many inflammatory genes.”

In healthy airways, under normal conditions, this signaling cascade is protective. The virus causes damage to the epithelial cells on the inside of our airways, and NF-kappaB helps produce a response that protects and repairs the cells. Then it shuts off. The problem arises when the response persists for too long, as it can in people who have compromised respiratory systems or who have respiratory systems that have been set, by previous trauma, to an epigenetic hair trigger. What begins as a simple repair, restoring the epithelial cells to their default condition, goes on too long and too intensively. There is thickening and scarring in the tissue just beneath the surface of the epithelium, as well as enlargement of myofibroblast cells and smooth muscle tissue.

It’s this thickening and hardening of the airways that is responsible for much of the deterioration in the quality of life of severe asthma and COPD sufferers. Each acute episode causes more damage, which can also make future episodes more likely. People grow weaker and weaker, and can ultimately die as a result of the diminished respiratory capacity.

If the innate response could be interrupted, however, a great deal of unnecessary damage could be prevented. Lives could be improved dramatically.

Toward a Treatment

For two decades, Brasier and his colleagues have been adding detail to the picture of this genomic pathway. The goal has been to improve their understanding of the pathway that results in airway remodeling, but also to use that understanding to develop drugs to disrupt it.

In the last few years, their search for a treatment has focused in on one key link in the genomic chain. It’s the Bromodomain 4 (BRD4) gene, and it is a key link between NF kappaB and the inflammatory genes that ultimately cause the airway remodeling.

“Nature has set up the pathway so that the inflammatory genes are poised to be activated,” says Brasier. “They’re waiting for a signal. The oxidative stress activates NF kappaB, which brings in BRD4 to the promoter. At that point the inflammatory genes fire off very quickly. Within an hour there is a high level of activity. It’s exactly what you want from a rapid innate response, but you only want to have it activated when you need it.”

Brasier and his colleagues hypothesized that if they could block the action of BRD4, the inflammatory genes would turn off, or never be turned on in the first place. They also knew that there were commercially available compounds that had been developed to block the action of the whole class of Bromodomain genes. So it was generically possible. The trick would be to develop a drug that was targeted to block BRD4 that wouldn’t have side effects that outweighed potential benefits.

That’s what they’ve done, working with expert colleagues at UTMB, including Dr. Jia Zhou, who is a skilled medicinal chemist; Dr. Erik Rytting, an expert in nanoparticle formulation; and Dr. Bing Tian, an expert in pharmacological testing in animal models. Together they’ve developed novel, potent and specific BRD4 inhibitors. Their compounds have been successfully tested in human cell lines as well as in mice. They dramatically reduce the scarring and stiffening processes that are responsible for airway remodeling.

The lab has received an Innovation Award from the pharmaceutical company Sanofi to develop the drug in an inhalable form. Brasier directs the UTMB Institute for Translational Science, whose mission is to advance UTMB’s clinical and translational capabilities with support from a Clinical and Translational Science Award from the National Institutes of Health. Both grants are given to speed the development of potential drugs that show exceptional promise.

“The strategy has been to design molecules that are like decoys,” says Brasier. “They bind to BRD4 and disrupt its binding to chromatin proteins, so BRD4 is unable to activate the inflammation process.”

Such a drug, says Brasier, probably would not be prescribed preventively, since the whole point is to inhibit the otherwise necessary and beneficial innate immune system. Instead, it would be prescribed when people with severe asthma or COPD are beginning to suffer from repeated exacerbations and decline in exercise capacity.

“What happens with these recurrent viral infections is that even after the virus is cleared, the activation of the inflammatory pathway persists and triggers the remodeling,” says Brasier. “But now, after the virus is cleared, certain people would be put on this drug, and that would prevent the long term loss of their lung function.”

If it is as effective as he hopes, says Brasier, it could make an enormous difference in the lives of people with these conditions. It wouldn’t cure asthma or COPD, but it would mitigate a lot of the long term damage that repeated, acute episodes do.

rasier and his colleagues are now preparing to test the inhalable form of the drug in mice. If it proves safe and effective, they will proceed to human testing. If that succeeds, and they make it through the complex gauntlet of FDA approval, Sanofi will bring the drug to market.

If at some point in the process this compound fails, they will return to what they know about the genomic pathway, to look for other points of intervention. In fact, they already have some other targets in mind, and there are other researchers coming at the problem from other angles. A group of colleagues at UTMB, says Brasier, is investigating ways to interrupt earlier in the sequence, hoping to prevent the oxidative stress from initiating in the first place.

“Our compounds certainly work better than the other compounds that are being advanced,” Brasier says. “They are more potent and more selective. They work very well in the preclinical models. So I am pretty confident, but you don’t know what you’re going to get when you get into humans. There is always some uncertainty in this. That is why we call it research.”