Aiming for Asthma Relief


Vol. 20 • Issue 7 • Page 12

ASTHMA Industry Report

Like an archer seeking a target’s center, researchers are aiming to develop more effective therapies for the 300 million people worldwide with asthma.1 The disease is tricky quarry, tantalizing researchers with clues to its heterogeneous origins.

Here are five studies leading asthma science down new and unexpected paths.

Genetic research

Results from the largest genetic study of asthma to date, the GABRIEL Consortium, found that one-third of children with asthma have variants on the ORMDL3/GSDMB gene, a number above what is seen in the general population. “Now that we have molecular evidence that it is a different syndrome, we might think about finding different ways to treat it,” said William O.C. Cookson, MA, MD, D.Phil, FRCP, F.Med.Sci, head of the division of respiratory sciences at Imperial College London.

The gene is up-regulated in people with asthma and may control sphingolipids that regulate inflammation. “There is a possibility that by altering sphingolipids or by trying different kinds of sphingolipids, we may be able to moderate the disease,” said Dr. Cookson, coordinator of GABRIEL.

Archive ImageA

But researchers first must determine the full function of the gene. In airway cell models, they will bind small interfering RNA (SIRNA) to the gene transcript to prevent it from being turned on by proteins. Then the cells will be exposed to bacteria, and their inflammatory response will be monitored.

“We anticipate that turning it off might result in reduced inflammation in those models,” Dr. Cookson said. “If we find that, we will be encouraged to look for directed therapies against what the gene does.” The “holy grail,” he said, will be finding a way to use the genetic information to prevent asthma development.

The Long-Acting Beta Agonist Response by Genotype (LARGE) study, on the other hand, assessed whether genotype could determine a patient’s response to long-acting beta agonists. Some previous studies had suggested that a subpopulation of people with asthma experience fewer benefits from LABAs and have an increased risk for severe exacerbations or death.2,3

Only ARG-ARG African American participants homozygous for arginine at the sixteenth amino acid position (B16 ARG/ARG) in the LARGE trial showed a genotype-specific effect: poorer peak flow performance when they were taking salmeterol. Analysis was limited because only 17 African Americans participated in the 87-person trial, but the results approached statistical significance.

“There still remain a lot of questions with regards to responsiveness to different therapies and stratifying genotype,” said lead author Michael E. Wechsler, MD, who is associate director of the Brigham and Women’s Hospital Asthma Research Center. “I suspect that there are other polymorphisms, other mutations in different genes that play a role.” A larger study to identify African American responders and non-responders to the drug is already under way.

Information from this trial could change how clinicians prescribe therapy, Dr. Wechsler predicted. Patients in the future will come in for a blood test and be genotyped to determine to which therapies their asthma will respond. And patients, he said, “are more likely to take their medications if the drug is working.”

Racial disparities

Severe asthma affects African Americans with a strength not seen in Caucasian populations: Blacks have four times the risk of hospitalization and five times the risk of mortality. But what accounts for the difference? A study out of the Severe Asthma Research Program found that severe asthma in black subjects was more associated with positive IgE levels, negative skin prick tests, and a strong family history of the disease.

“This is something that physicians right now should look at,” said Christy Gamble, DrPH, MPH, the study’s lead author. “By getting that information (about a patient), they can give them better treatment and a treatment plan.”

Researchers were unsure why positive IgE levels in black subjects significantly predicted severe asthma while five or more positive skin tests negatively predicted the disease since both tests evaluate allergic response. IgE serum levels might be detecting the presence of an additional measure that isn’t included in current skin test profiles, speculated Dr. Gamble of University of Pittsburgh.

The study also found that severe asthma in white subjects was more associated with comorbidities. But researchers think that black patients with severe asthma might be undiagnosed or underreporting their disease because black and white subjects with mild to moderate asthma reported comorbidities in similar numbers.

“Health care professionals need to make sure that they are testing other diagnoses or chronic ailments in these patients to make sure they are treated and are not exacerbating the effects of asthma or making their asthma worse,” Dr. Gamble said.

Asthma in pregnancy

The Asthma in Pregnancy Study examined how a mother’s diet influences respiratory disease development in her offspring. In women diagnosed with anemia during pregnancy, 17 percent of children had infant wheeze, and 22 percent were diagnosed with asthma by age 6.

“We were surprised at how strong the findings were,” said Elizabeth W. Triche, PhD, the study’s lead author. The association was even stronger when the mothers also had asthma. “One of the implications is that we can work harder to get mothers to properly take care of maternal diet and (we can) treat anemia in pregnancy more aggressively.”

But researchers also need to dig deeper into the relationship between anemia and asthma. “We don’t know whether anemia is a causal factor or whether it is a proxy for another causal factor,” said Dr. Triche, assistant professor in the department of community health/epidemiology at Brown University in Providence, R.I. Further studies are needed to look at folate and folic acid levels associated with anemia. “We know that folic acid supplementation can prevent things like neural tube (defects) so in effect those factors could be associated and explain the association between asthma and anemia.”

Immune response

The Inner-City Anti-IgE Therapy for Asthma study focused on whether omalizumab (Xolair, Genentech USA Inc. and Novartis Pharmaceuticals Corp.) could improve asthma control in inner-city children with moderate to severe asthma. In a 60-week trial, subjects randomized to receive omalizumab had 25 percent fewer days with symptoms and were able to significantly reduce their dose of inhaled corticosteroids and long-acting beta agonists.

But more importantly, spikes in asthma exacerbations typically seen during fall and spring were virtually eliminated. “We were just surprised to see those results,” said study co-author Rebecca Gruchalla, MD, PhD, professor of internal medicine and pediatrics and division chief of allergy and immunology at the University of Texas Southwestern Medical Center in Dallas. Viral infections – a major cause of autumn exacerbations – were similar in the omalizumab and placebo group, so the drug might have prevented an interaction between allergy and viral infections that induces asthma exacerbations. “That is why we are tailoring our next studies to address some of these interesting findings.”

Their primary question: “How is it doing it?” An upcoming Inner City Asthma Consortium mechanistic study will examine cells collected from participants’ blood to discover how omalizumab affects the immune response and to discern how allergens and viral infections relate to asthma.

With results from this year’s studies poised to help clinicians prescribe better therapy for patients, many clinicians are sure to echo the sentiments of Dr. Gruchalla: “These are very exciting times.”

Kristen Ziegler can be reached at [email protected].

References

1. Asthma Statistics. American Academy of Allergy, Asthma & Immunology. 2011. Available from: http://www.aaaai.org/media
/statistics/asthma-statistics.asp

2. Castle W, Fuller R, Hall J, et al. Serevent nationwide surveillance study: comparison of salmeteral with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ. 1993:Apr;306(6884):1034-7.

3. Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006:Jan;129(1):15-26.