Research Program > Major Advances

Major Advances

The American Asthma Foundation has funded a broad spectrum of new asthma initiatives, all directed at improving treatment, preventing, and finding a cure for this disease. Summarized below are the 26 studies that have led to major advances in understanding or treating asthma. Fourteen of these have drawn support from the biotech and pharmaceutical industries and four have advanced to clinical trials of new treatments for asthma.

  • Michael R. Blackburn, Ph.D.
    Using a Drug Necessary for Immunity to Help Asthma
    Biochemistry and Molecular Biology,
    University of Texas Health Sciences Center at Houston
  • Richard A. Bond, Ph.D.
    Turning the Treatment of Asthma on its Head
    Pharmaceutical Sciences, University of Houston
  • David W. Christianson, Ph.D.
    Blocking an Enzyme with Multiple Effects on Asthma
    Chemistry and Chemical Biology, University of Pennsylvania
  • David E. Clapham, M.D., Ph.D.
    Preventing the Airway Muscles from Squeezing the Airways During Asthma Attacks
    Cardiology, Children’s Hospital, Boston
  • Marco Conti, M.D.
    Bringing New Precision (and Fewer Side Effects) to the Treatment of Asthma
    Reproductive Biology, University of California, San Francisco
  • Michael Croft, Ph.D.
    Stopping Inflammation in Asthma by Blocking Immune Cell Communication
    Immunochemistry, La Jolla Institute for Allergy and Immunology
  • Joseph L. DeRisi, Ph.D.
    A Simple Method for Detecting Known Viruses Affecting Asthma
    Microbiology and Immunology, University of California, San Francisco
  • K. Christopher Garcia, Ph.D.
    New Information that Permits Designing Drugs for Asthma
    Molecular and Cellular Physiology, Stanford University
  • Eric Gouaux, Ph.D.
    Revealing the Structure of a Protein on Muscle Cells Opens the Path to Drug Design in Asthma
    Structural Biology, Oregon Health and Science University
  • William Harnett, Ph.D.
    Finding Proteins in Worms to Treat Asthma
    Pharmacy and Biomedical Sciences, University of Strathclyde
  • V. Michael Holers, M.D.
    Taming Natural Defenses that Cause Harm in Asthma
    Rheumatology, University of Colorado Health Sciences Center
  • Sven-Eric Jordt, Ph.D.
    Control of Asthma by Nerves in the Lung
    Pharmacology, Yale University School of Medicine
  • Christopher L. Karp, M.D.
    How Insects in House Dust Activate Asthma
    Pediatrics and Molecular Immunology,
    Cincinnati Children’s Hospital Research Foundation
  • Robert J. Lefkowitz, M.D.
    “Arresting” Inflammation in Asthma Biochemistry and Medicine, Duke University
  • Roderick MacKinnon, M.D.
    The Structure of a “Channel” on Airway Muscle Cells Opens the Path to New Therapies
    Molecular Neurobiology and Biophysics, Rockefeller University
  • Victor Nizet, M.D.
    A New Target for the Treatment of Asthma
    Pediatrics and Pharmaceutical Sciences, University of California, San Diego
  • Eric N. Olson, Ph.D.
    Controlling Genes that Control Asthma
    Molecular Biology, University of Texas Southwestern Medical Center at Dallas
  • Daphne Preuss, Ph.D.
    The Role of Pollens: More Than We Thought
    Molecular Genetics and Cell Biology,
    University of Chicago/Howard Hughes Medical Institute
  • Danuta Radzioch, Ph.D.
    Treatment of Asthma with a Drug Previously Used Only on the Skin
    Infection and Immunity Axis, McGill University
  • Kodi S. Ravichandran, Ph.D.
    Proper Burial for Dying Cells in the Lung Prevents Asthma
    Microbiology, University of Virginia, Charlottesville
  • Kevan M. Shokat, Ph.D.
    Synergy Between Investigators Opens New Approach to Asthma
    Chemical Biology, University of California, San Francisco
  • Satish K. Srivastava, Ph.D.
    Turning an Old Diabetes Drug to New Use in Asthma
    Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston
  • Jonathan S. Stamler, M.D.
    Restoring the Ability to Keep Airways Open in Asthma
    Biochemistry, Duke University
  • Mary E. Sunday, M.D., Ph.D.
    Blocking a Protein in the Airways that Promotes Asthma
    Pathology and Pathology Research, Duke University
  • Jenny P-Y Ting, Ph.D.
    Newly Discovered Pathways to Inflammation
    Microbiology and Immunology, University of North Carolina at Chapel Hill
  • Ralph Weissleder, Ph.D.
    Visualizing the Lungs During an Attack of Asthma
    Radiology, Harvard Medical School

  • Michael R. Blackburn, Ph.D.

    Using a Drug Necessary for Immunity to Help Asthma
    Biochemistry and Molecular Biology,
    University of Texas Health Sciences Center at Houston

    A genetic cause of immune deficiency in children is the lack of an enzyme called adenosine deaminase (ADA), and patients lacking ADA can be treated by replacing the enzyme. Dr. Blackburn has found that treatment with ADA unexpectedly reduces lung inflammation in animal models for asthma by reducing levels of adenosine, one of the targets of the ADA enzyme. Dr. Blackburn’s AAF-sponsored studies also led him to define a molecule on the surface of cells that binds to adenosine, and this has provided a new target for the treatment of asthma. Based on his work, major pharmaceutical companies are testing a new drug for the treatment of asthma.
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  • Richard A. Bond, Ph.D.

    Turning the Treatment of Asthma on its Head
    Pharmaceutical Sciences, University of Houston

    Many patients with asthma inhale drugs called ‘β-agonists’, such as albuterol, which open the airways. Drugs called ‘β-blockers’ oppose the action of β-agonists. Although β-blockers have long been used for diseases such as hypertension, they are usually forbidden in patients with asthma because they may make asthma worse. From his studies of animals however, Dr. Bond has surprising evidence that this may not be true in the long run; asthma may instead improve with low daily doses of β-blockers. Dr. Bond and his colleagues are now testing low-dose β-blockers in humans with asthma. If this works as it does in animals, it will turn the treatment of asthma on its head—small doses of what was once thought a ‘poison’ in asthma will instead be used to treat it.
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  • David W. Christianson, Ph.D.

    Blocking an Enzyme with Multiple Effects on Asthma
    Chemistry and Chemical Biology, University of Pennsylvania

    The lungs of both mice and humans with asthma have an increase in an enzyme called arginase, which is present only in low levels in healthy lungs. The activity of this enzyme has multiple effects that make asthma worse, namely closing airways, increasing secretions in the lungs, and causing permanent scarring in airways. For these reasons, it is desirable to find drugs that block the activity of arginase. Dr. Christianson is seeking to do just this by determining the molecular structure of arginase. This will allow him to develop drugs that bind to arginase and block its activity. The ultimate goal is to develop drugs that can be inhaled to prevent or reverse an attack of asthma.
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  • David E. Clapham, M.D., Ph.D.

    Preventing the Airway Muscles from Squeezing the Airways During Asthma Attacks
    Cardiology, Children’s Hospital, Boston

    The sudden difficulty in breathing that occurs in asthma is due to muscles around the airways, which tighten and squeeze the airways. This muscle tightening requires the entry of calcium into muscle from the surrounding tissues. Dr. Clapham has developed a treatment for asthma that blocks the entry of calcium into airway muscle cells. He has cofounded a company that will continue his work to test the use of these drugs in asthma.
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  • Marco Conti, M.D.

    Bringing New Precision (and Fewer Side Effects) to the Treatment of Asthma
    Reproductive Biology, University of California, San Francisco

    For many years asthma was treated with theophylline, a drug that is related to caffeine. But the use of theophylline was limited by its side effects, some of which can be dangerous. Based in part on Dr. Conti’s work, several drug companies have developed drugs that are more selective in their action and should thus have fewer side effects. One of these is in advanced (Phase-3) clinical trials. Dr. Conti’s AAF-supported work has shown the feasibility of making drugs that are even more selective in their action, but just as effective, further reducing side effects. Two pharmaceutical companies have developed patents based on this work.
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  • Michael Croft, Ph.D.

    Stopping Inflammation in Asthma by Blocking Immune Cell Communication
    Immunochemistry, La Jolla Institute for Allergy and Immunology

    In asthma, the immune system becomes overactive in the lungs, causing inflammation and damage to the lungs. Dr. Croft found a new way to block the overactive immunity in asthma by blocking proteins (called OX40 and OX40L) on the surface of immune cells. These two proteins interact with each other, allowing the immune cells to “talk” to each other, sending signals to activate immunity. Dr. Croft’s work has led Genentech, in collaboration with Roche Pharmaceuticals, to pursue a new therapy that will prevent the interaction between OX40 and OX40L. This approach is now in clinical trials.
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  • Joseph L. DeRisi, Ph.D.

    A Simple Method for Detecting Known Viruses Affecting Asthma
    Microbiology and Immunology, University of California, San Francisco

    Asthma attacks are often brought on by viral infection, but we understand too little about which viruses are especially prone to cause an attack. To solve this problem, Dr. DeRisi and his colleagues used cutting-edge technology to develop a tiny chip that can detect all known viruses that infect humans. This is being used to track viral infection in asthma. It has also been important in other illnesses and was used to first identify the SARS virus.
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  • K. Christopher Garcia, Ph.D.

    New Information that Permits Designing Drugs for Asthma
    Molecular and Cellular Physiology, Stanford University

    Attacks of asthma are launched and sustained by molecules called ‘cytokines’, which circulate through the body to activate the immune system. This attack is useful for defending against infections, but in asthma the response goes astray, causing unnecessary inflammation of the lungs and narrowing of the airways. To block this response in the lung, it would be useful to have drugs that prevent the cytokines from binding to immune cells in the lung. To this end, Dr. Garcia, has defined the exact shapes of molecules on the cell surface that can bind to cytokines that cause asthma. This allows chemists to design drugs that will block the binding by cytokines, arresting the immune responses that cause asthma. In fact, a 2008 AAF grant to Gregory Verdine, at Harvard proposes just that—to develop new drugs for asthma based on Garcia’s work.
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  • Eric Gouaux, Ph.D.

    Revealing the Structure of a Protein on Muscle Cells Opens the Path to Drug Design in Asthma
    Structural Biology, Oregon Health and Science University

    In asthma, the muscles that surround the airways contract, closing the airways. The contracture of these muscles is controlled by proteins that reside on the surface of muscle cells and control the flow of ions (potassium, calcium) through the cell membrane. In his AAF-sponsored studies, Dr. Gouaux described for the first time the structure of one of these protein, called the ATP-gated P2X(4) ion channel. Knowledge of the structure of this protein greatly facilitates the design of drugs that might alter its activity and thus benefit asthma. Dr. Gouaux is using this information to screen for new drugs in the treatment of asthma.
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  • William Harnett, Ph.D.

    Finding Proteins in Worms to Treat Asthma
    Pharmacy and Biomedical Sciences, University of Strathclyde

    Prior studies have suggested that infection with certain parasitic worms may protect against asthma. Dr. Harnett has been studying molecules from parasitic worms in order to understand the mechanisms of this effect. From one worm, he isolated a protein that can inhibit inflammation, and he has now identified much smaller molecules that mimic the effects of the worm component in inhibiting inflammatory cells in vitro. This opens a pathway that might allow the use of such small molecules in therapy, instead of testing the use of worms.
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  • V. Michael Holers, M.D.

    Taming Natural Defenses that Cause Harm in Asthma
    Rheumatology, University of Colorado Health Sciences Center

    Dr. Holers has shown that natural defenses, normally used against infections, may cause harm in asthma. These defenses are collectively called the complement system. Dr. Holers has shown in animals that blocking one part of this defense system prevents inflammation in asthma. The biotech company Taligen Therapeutics is developing this approach for future testing in humans.
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  • Sven-Eric Jordt, Ph.D.

    Control of Asthma by Nerves in the Lung
    Pharmacology, Yale University School of Medicine

    It has long been known that stimulation of nerves in the lung can open and close the airways, but Dr. Jordt finds that nerves also control inflammation in the lung. In particular, there is an important role in the lung for nerves that were once thought only to send signals directly to the brain (such as pain signals). It is now clear that these nerves do more than that. In particular, when these nerves are stimulated in a specific manner, they release chemicals into the lung that promote inflammation and asthma. In animal models for asthma, Dr. Jordt has tested drugs that block this role of nerves in inflammation. This new approach strongly inhibits asthma.
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  • Christopher L. Karp, M.D.

    How Insects in House Dust Activate Asthma
    Pediatrics and Molecular Immunology,
    Cincinnati Children’s Hospital Research Foundation

    Asthma is strongly associated with exposure to dust mites, tiny insects that live in bedding, carpeting, and cloth furniture. It has been known for some time that people with asthma often have dust mite allergies, and this contributes to asthma. Allergies result from a harmful immune response against otherwise innocuous proteins (allergens). For most allergens, it is unclear why they generate this harmful response, but Dr. Karp has shown why this is so in the case of dust mites: these mites release a protein, called Der p 2, that helps to activate the immune responses. The immune system has special sensors that signal the presence of microbes (such as bacteria), activating the immune system to respond to infectious threats. The dust mite Der p 2 protein mimics a key component of an immune sensor that normally signals the presence of bacteria. Exposure to Der p 2 activates the sensor, setting off potent immune responses to dust mites.
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  • Robert J. Lefkowitz, M.D.

    “Arresting” Inflammation in Asthma
    Biochemistry and Medicine, Duke University

    The cells that cause inflammation in asthma express proteins called β-arrestins.
    Dr. Lefkowitz has previously shown that heart and vascular diseases involve β-arrestins. As part of his AAF Award, he and his colleague, Julia Walker, demonstrated in animals that β-arrestins are required for the development of asthma. This led to a patent regarding inhibition of β-arrestins in asthma, and Dr. Walker is pursing studies of how arrestins might be blocked to prevent asthma.
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  • Roderick MacKinnon, M.D.

    The Structure of a “Channel” on Airway Muscle Cells Opens the Path to New Therapies
    Molecular Neurobiology and Biophysics, Rockefeller University

    In an attack of asthma, the muscles around the airways tighten, narrowing the airways and reducing the flow of air. Control of the airway muscles, therefore, is a major part of asthma therapy. The contraction of these muscles is controlled by the flow of potassium in and out of the cell through tunnels in the cell wall called “channels.” One type of channel, the
    BK channel, is particularly important in asthma. Dr. MacKinnon has, for the first time, determined the structure of most of the BK channel (the portion that lies inside the cell). The structure reveals how the channel is opened or closed depending on the level of calcium inside the cell. Knowing the structure of the BK channel will greatly advance the design of drugs to relax the airway smooth muscles, reversing or preventing an asthma attack.
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  • Victor Nizet, M.D.

    A New Target for the Treatment of Asthma
    Pediatrics and Pharmaceutical Sciences, University of California, San Diego

    Asthma is marked by chronic inflammation in and around the airways. Dr. Nizet is studying molecules inside inflammatory cells called hypoxia-inducible transcription factor-1α (HIF1α), so named because it was first discovered as a protein that increases in cells when they lack oxygen. HIF1α proves to be an important molecule in the regulation of inflammation.
    Dr. Nizet has shown that mice deficient in this molecule are highly resistant to asthma, and he has been able to block asthma in mice by giving them an inhibitor of HIF1α, opening the way to new methods for the treatment and/or prevention of asthma.
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  • Eric N. Olson, Ph.D.

    Controlling Genes that Control Asthma
    Molecular Biology, University of Texas Southwestern Medical Center at Dallas

    The closing of airways in asthma involves inappropriate contraction of airway muscles, which also grow in size and strength. These changes are genetically regulated, and
    Dr. Olson has identified molecular pathways in the cell that control the genetic changes. These studies have the potential to lead to the development new therapies, including drugs that could mimic the actions of corticosteroids with fewer side effects.
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  • Daphne Preuss, Ph.D.

    The Role of Pollens: More Than We Thought
    Molecular Genetics and Cell Biology,
    University of Chicago/Howard Hughes Medical Institute

    Pollens are a major trigger to allergy and asthma. Testing for allergy to pollens involves skin tests with extracts from the plants that produce pollens. Dr. Preuss and her colleagues have shown that the preparation of these extracts often removes the parts of allergens that are most important in causing allergy and asthma. She has developed new tests that can rapidly, accurately, and inexpensively detect allergies using only a small amount of blood. This holds great potential for defining allergies in asthma and for customizing therapy to each individual.
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  • Danuta Radzioch, Ph.D.

    Treatment of Asthma with a Drug Previously Used Only on the Skin
    Infection and Immunity Axis, McGill University

    Dr. Radzioch’s studies led her to test a compound called S28463 (a.k.a. resiquimod), developed by 3M Pharmaceuticals. This drug is clinically used as a topical treatment for skin conditions, including skin cancer. When Dr. Radzioch gave S28463 to animals, it almost completely blocked the development of asthma. In partnership with 3M and Grace Pharmaceuticals, she is now conducting studies monitoring the safety of this compound so clinical trials can start in asthma.
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  • Kodi S. Ravichandran, Ph.D.

    Proper Burial for Dying Cells in the Lung Prevents Asthma
    Microbiology, University of Virginia, Charlottesville

    There is a constant turnover of cells in most tissues in the body, and this is true also for cells that line the airways. The cells that die as part of the turnover have to be cleared without harm to the rest of the tissue. Uncleared dying cells can set off inflammation, and inflammation in the lungs can lead to asthma, so this inflammation must be controlled. In his AAF-sponsored studies, Dr. Ravichandran demonstrated that when airway cells die, they can be removed by neighboring airway cells, and this cell clearance process causes the healthy airway cells to suppress inflammation. This discovery opens a new chapter in our understanding of how lung inflammation is controlled. Dr. Ravichandran is working to understand the molecular players that regulate cell clearance and airway inflammation so that these can be harnessed to prevent or to treat asthma.
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  • Kevan M. Shokat, Ph.D.

    Synergy Between Investigators Opens New Approach to Asthma
    Chemical Biology, University of California, San Francisco

    As part of a broad approach to blocking the activation of inflammatory cells, Dr. Shokat discovered a drug that blocks the breakdown of GSNO, the very molecule that Dr. Jonathan Stamler found to be reduced in asthma (below). The two investigators compared notes at the annual meeting of AAF investigators, and Dr. Shokat is now working with a former trainee of Dr. Stamler’s (now on the faculty of UCSF with Dr. Shokat) to develop this and other ways of preventing the loss of GSNO in asthma. Dr. Shokat has founded a company, Intellikine, which is actively pursuing these and other approaches to asthma.
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  • Satish K. Srivastava, Ph.D.

    Turning an Old Diabetes Drug to New Use in Asthma
    Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston

    In studies of mice, Dr. Srivastava has found that a drug once tried without success in the therapy of diabetic neuropathy does much better in treating asthma. The drug belongs to a family of agents called aldose reductase inhibitors. Dr. Srivastava has found that these drugs not only reduce inflammation, but also reduce the type of immunity that is associated with asthma. They also effectively reduce asthma in mice when given either by mouth or inhaled into the nose. Because these drugs were previously evaluated in large trials of humans with diabetes and found to be relatively safe, they should be readily available for clinical trials in patients with asthma. Indeed, Dr. Srivastava’s group is currently planning for human trials with one of these drugs, fidarestat.
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  • Jonathan S. Stamler, M.D.

    Restoring the Ability to Keep Airways Open in Asthma
    Biochemistry, Duke University

    Cells in normal airways make a small molecule called GSNO, which keeps the airways open. Dr. Stamler and his colleagues found that GSNO falls to low levels in asthma, and that asthma in animals is improved when GSNO is restored. Based on this work,
    N30 Pharma has initiated clinical trials of GSNO in patients with asthma.
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  • Mary E. Sunday, M.D., Ph.D.

    Blocking a protein in the airways that promotes asthma Pathology and Pathology Research, Duke University

    Asthma involves inflammation of the lung airways. By studying asthmatic responses to allergens and air pollutants in mice, Dr. Sunday has found that airway inflammation is promoted by a protein made locally in the airways, called ‘gastrin-releasing peptide’ (GRP). By blocking GRP, Dr. Sunday markedly reduced both airway inflammation and airway tightening in mice with asthma. The effect of GRP blockade was substantially greater than that observed with steroid treatment in the same mouse models. Because of these beneficial effects of GRP blockade in mice, this new treatment is being considered for testing in humans with asthma.
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  • Jenny P-Y Ting, Ph.D.

    Newly Discovered Pathways to Inflammation
    Microbiology and Immunology, University of North Carolina at Chapel Hill

    A few years ago, Dr. Ting described a group of related proteins that are used throughout the animal and plant kingdoms to control immunity and inflammation. She called these CATERPILLER proteins, recently named NLR proteins. Her studies have led to the discovery of how these proteins work and their role in asthma. She has entered into an agreement with a major biotechnology company to apply this work to asthma therapies.
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  • Ralph Weissleder, Ph.D.

    Visualizing the Lungs During an Attack of Asthma
    Radiology, Harvard Medical School

    To better understand what causes asthma, it would be useful for scientists to see exactly what happens during asthma: how the airways close and open, what changes occur in the cells and fluids in airways, and what changes occur in the cells and enzymes that surround the airways. Dr. Weissleder is a leader in exploring new approaches to look at living tissue and, with his Award from the AAF, he has turned his attention to the asthmatic lung, bringing new understanding to the changes that occur in asthma. Dr. Weissleder has begun with studies of rodents, but his work will also have future application to humans with asthma.
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