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Asthma attack prevention proposal awarded NIH New Innovator grant

MD Anderson-developed aerosol enlists good inflammation to head off bad inflammation

MD Anderson News Release 09/30/13

Research on an aerosol that jump-starts a rapid immune response to stifle viral respiratory infections before they can provoke asthma attacks has earned major funding from the National Institutes of Health.

The NIH named Scott Evans, M.D., associate professor of Pulmonary Medicine at The University of Texas 
MD Anderson Cancer Center, a New Innovator award winner, part of the institute’s High Risk High Reward program to address major challenges in biomedical research.

“Asthma affects 8 percent of Americans – 26 million adults and children – and its incidence continues to grow for reasons we don’t fully understand,” Evans said. “However, research shows that 80 percent of all asthma attacks are caused by respiratory viral infections which cause damaging allergic inflammation in the lungs.”

“Our lab has found that if we induce the right kind of inflammation, we can protect lungs against infections and prevent harmful inflammation,” Evans said.

“By treating with our novel therapeutic to trigger lung defenses at the first sign of infection, such as a runny nose or sneezes, we can prevent the infection from progressing to the lungs,” Evans said.  “We also have reason to believe that we might be able to reprogram lung cells to prevent long-term, irreversible asthmatic progression.”

The New Innovator grant, $2.4 million spread over five years, will fund preclinical research in lung cells and mouse models that is expected to translate to clinical trials to prevent asthma attacks.

Aerosol triggers innate immunity to squelch infections

Evans and colleagues previously showed that the inhaled aerosol stimulates an innate immune response in the lungs of mice, protecting them against otherwise lethal pneumonias caused by bacterial, viral or fungal pathogens, including treatment-resistant bacteria, and potential bioterror agents such as anthrax.

“We found we could protect against anything we’ve ever tested,” he said.

Since the first experiments using an extract of a bacterium that causes ear and sinus infections in children, Evans and colleagues have developed a synthetic version that’s more amenable to use as a drug.  A first-in-humans phase I trial is expected to begin soon, and subsequent clinical trials in patients with leukemia and in patients with asthma have already received funding through other grants.

Inducible resistance

Allergic inflammation has long been identified as a culprit in acute asthma attacks and long-term damage to airways.  Inflammation is a primary target of asthma treatment, but anti-inflammatory medicines don’t appreciably slow disease progression, Evans said.

Viruses invade the lining of the lungs – the epithelial tissue – and launch an inflammatory immune response that, left to its own devices in susceptible people, makes the lungs vulnerable to future attacks and promotes asthma progression.
The aerosol developed by Evans and colleagues simulates an infection that stimulates an innate immune system response – the fast  action component of the immune system that swiftly deploys proteins and reactive oxidative species to destroy invading pathogens.

Ramping up the innate immune system before a viral infection is well-established starts wiping out the infection within hours, their research has found. They call this “good” inflammatory response inducible resistance.

An adaptive immune response, triggered by the innate immune activation, launches a more targeted pathogen-specific response that “remembers” the invader forever but can take days to fully respond.

Crucial components identified, synthesized

From earlier experiments, Evans pinpointed the crucial components of the response to the bacterial aerosol that actually launched the innate immune inflammatory response.  He combined two synthetic ligands that bind to two toll-like receptor proteins, igniting innate immunity in a much more robust manner than would be achieved by a single stimulus alone.

The NIH program “allows researchers to propose highly creative research projects across a broad range of biomedical research areas that involve inherent risk, but have the potential for high rewards,” NIH Director Francis Collins, M.D., Ph.D., said in a statement announcing the awards.

The effort includes NIH Pioneer, New Innovator, Transformative Research and Early Independence Awards. Total funding in 2013 is $123 million, which represents contributions from the NIH Common Fund and multiple NIH institutes and centers.  

Evans and others involved in the research, including Burton Dickey, M.D., chair of the Pulmonary Medicine, formed a company called Pulmotect, LLC, which has licensed the technology from MD Anderson. These arrangements are managed in accordance with MD Anderson conflict-of-interest policies.

© 2014 The University of Texas MD Anderson Cancer Center