Disease pathways lead to possible new treatment for severe asthma

Here’s a sobering thought: Nearly half of Americans with severe asthma do not respond to conventional drugs, leaving them with few ways to minimize the often-debilitating symptoms of the chronic disease. But researchers at NHLBI have developed a new treatment that has the potential to dramatically change that: A synthetic peptide that mimics the work of a protein, called apolipoprotein, that appears to reduce inflammation in the lungs and improve their ability to function normally.

The researchers made the discovery by studying the pathways of asthma, leading them to conclude that, despite the similarity in patient’s symptoms, the severe form of the disease could have several genetic root causes, each resulting in different responses to treatment.

Microscopic images of the lungs of mice

Effect of the 5A apoA-I mimetic peptide on the lungs and the airway hyperreactivity in mice with asthma.

About 25 million people in the United States suffer from asthma, which is marked by inflammation and narrowing of the airways and causes wheezing, coughing, chest tightness and shortness of breath. It affects people of all ages, but it most often starts during childhood—seven million children have the disease—and it disproportionately affects minorities and families living at or below the poverty line. The condition can greatly reduce a person’s quality of life and is a major contributing factor to absences at school and work. Severe asthma attacks may require emergency room visits and hospitalizations, and they can be fatal.

In an effort to understand why some people respond to some asthma medications and others do not, researchers started with the basics. “By studying the pathways of the disease, we identified a new biological mechanism that leads to asthma,” explained Stewart J. Levine, M.D., Chief of the NHLBI Laboratory of Asthma and Lung Inflammation.

About half asthmatics have type 2-high asthma, while the others have type 2-low asthma. Type 2-high asthma is caused by an increase in the lungs and blood of inflammatory cells called eosinophils, Levine explained. But people with type 2-low asthma do not have these increased levels of eosinophils. This suggests, he said, that their asthma develops through other pathways—for instance, neutrophils, another type of inflammatory cell.

These differences, it turns out, have profound implications for treatment. For some patients with severe type 2-high asthma, standard medications, such as inhaled steroids and long-acting bronchodilators, do not help, but antibody treatments, a form of immunotherapy, do. Unfortunately, for patients with severe type 2-low asthma who do not respond to standard drugs, effective medications have not been available. This could change with the development of a new synthetic peptide, an inhaled formulation of an apolipoprotein, according to Levine.

Charts of the administration of the synthetic peptides

Administration of apolipoprotein A-I mimetic peptides or human apolipoprotein A-I to mice reduces airway inflammation.

Apolipoproteins – proteins in blood that typically transport fats in and out of cells – have names that are akin to zip codes – they basically identify the genes that encode or produce them. For instance, in humans, apolipoprotein A-I is encoded by the APOA1 gene.

Scientists at Levine’s lab discovered that apolipoproteins also regulate the severity of asthma. This gave them the idea that apolipoprotein A-I, a protein with a specific role in the metabolism of lipids, might have a protective effect against asthma.

In 2009, Xianglan Yao, M.D., Ph.D., a senior scientist in Levine’s lab, began a collaboration with Alan Remaley, M.D., Ph.D., NHLBI senior investigator, who invented a small synthetic protein, the 5A apolipoprotein A-I mimetic peptide, as a new treatment for atherosclerotic vascular disease. Yao was exploring its potential for treating asthma.

“For our experiments, we selected asthma that is induced by house dust mites because it is a common indoor allergen that causes asthma,” Levine explained. “We showed that administration of the 5A apolipoprotein A-I mimetic peptide reduced the manifestations of experimental asthma in mice that had been exposed to house dust mites.”

Then the researchers performed the experiments with mice that lack the apolipoprotein A-I gene, and therefore did not have any apolipoprotein A-I in their bodies. The results were clear. Those mice had more inflammation in their lungs.

That was not the only discovery. “We showed that inhalation of the 5A apolipoprotein A-I mimetic peptide prevented allergic lung inflammation in asthmatic mice that lacked their own apolipoprotein A-I,” said Levine. “The next step was to know if the apolipoprotein A-I played a similar role in asthmatic patients.” And research conducted by Levine’s colleagues Amisha Barochia, M.B.B.S., M.H.S. and Maryann Kaler, C.R.N.P. showed it did: higher serum levels of apolipoprotein A-I in asthmatic patients were associated with better lung function.

“These results support our proposal that an inhaled form of the 5A apolipoprotein A-I mimetic peptide be moved forward to clinical trials to find out if the treatment is safe and effective,” said Levine.

Late last year, NHLBI gave a Small Business Innovation Research (SBIR) grant to develop an inhaled formulation of the 5A apolipoprotein A-I mimetic peptide, which will be assessed by the Food and Drug Administration (FDA) for use in humans. It will take a few more years to complete the testing needed for FDA approval. Then the main clinical trials, said Levine, can begin at the NIH Clinical Research Center.

 

REFERENCES:
https://www.nhlbi.nih.gov/news/2018/disease-pathways-lead-possible-new-treatment-severe-asthma
https://www.nhlbi.nih.gov/health-topics/asthma
https://www.nhlbi.nih.gov/science/asthma-and-lung-inflammation
https://www.nhlbi.nih.gov/news/2018/disease-pathways-lead-possible-new-treatment-severe-asthma#
https://www.nhlbi.nih.gov/news/2018/disease-pathways-lead-possible-new-treatment-severe-asthma#
https://www.nhlbi.nih.gov/grants-and-training/funding-opportunities-and-contacts/small-business-program