Could a newly identified cell type lead to the cure for cystic fibrosis and more?

Newly identified, rare pulmonary ionocytes (green) dot the landscape of ciliated cells (white) of the mouse lung airway lining.
Credit: Montoro et al./Nature 2018

These cells appear to be the primary source of activity of the gene responsible for multiorgan disease

 

 

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Defeating asthma attacks by going small

An invisible particle enters your lungs. The next thing you know breathing becomes difficult. You are having an asthma attack. Asthma is one of the most common and difficult to endure chronic conditions.

About 30 million Americans experience asthma attacks and 3 million have a severe, therapy-resistant form of the disease. In some cases, the condition can be fatal.

“Despite the prevalence of asthma around the world, therapy for this condition has not significantly changed, with a few exceptions, in the last 70 to 80 years,” said Dr. David Corry, professor of medicine-immunology, allergy and rheumatology at Baylor College of Medicine. “For the most part, we are still treating the symptoms of the disease, not the underlying causes. In this work we present a novel new way to target a pathway we think is at the core of this allergic condition.”

Dr. David Corry

Current treatments attempt to relieve typical asthma symptoms, namely the constriction of the airways so patients can breathe easily. Treatments may also include steroids to shut down the inflammation that scientists have thought for many decades underlies airway constriction. Inflammation of the airway leads to shortness of breath, and that can make people panic and head to the emergency room.

Corry’s laboratory has been studying asthma for about 20 years. One of their interests is to better understand the molecular pathways that drive airway constriction.

The makings of an asthma attack

An asthma attack is anything but a simple event. It begins when environmental factors – allergens – enter the lungs and activate a chain reaction of molecular pathways that set off the development of the disease. Allergens activate immune cells, recruiting them to the lungs and leading some of them to produce a strong IgE antibody response and others to secrete immune mediators called cytokines. Cytokines IL-4 and IL-13 in particular are required for asthma to happen. These cytokines activate another molecule, transcription factor STAT6, that drives the expression of a number of genes ultimately leading to the exaggerated contraction of the airways that causes the much feared shortness of breath.

Mice that are genetically engineered to lack STAT6, also lack the responses triggered by the IL-4/IL-13/STAT6 interaction and are completely resistant to asthma attacks.

“STAT6 is at the epicenter of the immune responses that mediate asthma, so we looked for a means to block STAT6 activation,” said Dr. J. Morgan Knight, post-doctoral fellow in the Corry lab. “To activate STAT6, IL-4 and IL-13 bind to their corresponding receptors on immune cells. These receptors share a critical subunit called IL4R-alpha that activates STAT6.  However, additional research from our lab has shown that completely different receptors also can activate STAT6.  So, we focused our efforts on developing a small-molecule that would bind to and inhibit STAT6 activity directly.”

David defeats Goliath

Such efforts are no small feat. Corry, Knight and their colleagues had to design a small molecule capable of specifically targeting STAT6, which is inside the cells of the lungs, without also triggering unwanted side effects.

“After years of work, we succeeded,” said Knight. “We chemically synthesized a small molecule called PM-43I that can inhibit STAT6-dependent allergic airway disease in mice. Moreover, PM-43I reversed preexisting allergic airway disease in mice with a minimum dose of 0.25 ?g/kg. Importantly, PM-43I was efficiently cleared through the kidneys and had no long-term toxicity.”

We concluded that PM-43I represents the first of a class of small molecules that may be suitable for further clinical development as a therapeutic drug against asthma,” Knight said.

Dr. J. Morgan Knight

One major advantage of developing PM-43I as an asthma drug that specifically targets a path that is required for the disease is that people probably would not need steroid treatments at the same time, which is what current asthma medications sometimes are paired with. Steroids shut down inflammation, but also other immune responses, such as the body’s ability to fight an infection. The researchers’ work shows that in fact treatment with their small molecule can control the asthma without impairing the mice’s ability to fight pathogens.

“This is important because there is a higher incidence of pneumonia in people with asthma, presumably because of the steroids they take,” Corry said. “Steroids drive down all the immune system, but our small molecule specifically targets the pathway that leads to asthma, uncompromising the other pathways that allow the body to fight disease. We anticipate that patients treated with our small molecule would not need steroids as our treatment alone would be able to control the asthma. Consequently, these patients’ ability to fight infections would not be affected.”

Although other groups have developed monoclonal antibodies that effectively target IL4R-alpha and inhibit STAT6-dependent allergic disease, and these antibodies are close to be approved by the Food and Drug Administration, the researchers think that their small-molecule approach offers unique advantages when compared with the much larger antibodies.

Formula of the small molecule PM-43I. Courtesy of Dr. D. Corry.

“We think that our small molecule offers the option of being easier to make and less expensive than the monoclonal antibody approach,” Corry said. “Also, people might develop sensitivity or tolerance to the monoclonal antibody treatment. On the other hand, our compound is a chemically synthesized very small molecule, so we think there is a smaller chance that people would develop a sensitivity to it.  In addition, we think that our small molecule is better able to block STAT6 than the antibodies.”

“I am most excited about the potential to really affect disease,” Knight said. “I think that if our small molecule approach can help the lung resolve the chronic inflammation that is driving the asthma attacks, it might be possible to also resolve their condition.”

“The ideal way to manage any disorder is to get at the root, the fundamental underlying cause. In asthma, we can break it down into endogenous factors, in this case inflammatory, where STAT6 comes in, and then the environmental, and that is the nearly invisible particles,” Corry said. “Ideally, we would target both of these at the same time.”

This is our first shot at applying a modern understanding of disease to therapy. That’s what I am most excited about, developing a modern approach to treat this common disorder,” Corry said.

The researchers are working toward moving this small molecule to the next stage of testing in clinical trials in order to one day make it available to people.

Learn more: David vs Goliath: how a small molecule can defeat asthma attacks

 

 

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A new treatment for severe asthma

Parameswaran Nair, professor of medicine at McMaster and staff respirologist at St. Joseph’s Healthcare Hamilton

Researchers from McMaster University and the Firestone Institute for Respiratory Health at St. Joseph’s Healthcare Hamilton, together with colleagues at other partnering institutions, have developed a new method to treat severe asthma.

In a study of over 200 participants with severe asthma, the new treatment was shown to have improved asthma symptoms and lung function, while reducing the need for corticosteroids by up to 70%.

According to Statistics Canada, eight per cent of Canadians aged 12 or older – approximately 2.4 million people – have been diagnosed with asthma. Of that, approximately 25% are considered to be severe cases of asthma.

Current treatments for severe asthma often include high doses of corticosteroids, such as prednisone, to control exacerbations. Reducing the need for corticosteroids with alternative treatments is preferable, since these medications are associated with serious side effects from prolonged use – including multi-organ toxicities and immunosuppression.

Parameswaran Nair, professor of medicine at McMaster and staff respirologist at St. Joseph’s Healthcare Hamilton, along with a team of researchers found that an antibody called dupilumab is effective in treating severe asthma in place of high doses of prednisone.

The results were published in the New England Journal of Medicine, one of the world’s most influential medical publications.

Researchers sought participants who had been using oral corticosteroids (prednisone) to treat severe asthma for at least six months prior to the study. In addition to their standard regimen of corticosteroids, patients received either dupilumab or a placebo during the 24 week trial. The corticosteroid dose was gradually reduced during weeks four to 20, and maintained at a low level for the final four weeks.

“The ability of dupilumab to increase lung function as markedly as it did in this study, even in the face of [corticosteroid] withdrawal, indicates that it appears to be inhibiting key drivers of lung inflammation,” the researchers noted.

Dupilumab works to treat asthma by blocking two specific proteins (called interleukin-4 and interleukin-13) that are associated with inflammation of the airways.

This technique was based on Nair’s previous research, (published in the New England Journal of Medicine in 2009 and in 2017). Those studies found that blocking another protein, interleukin-5, allowed patients with high eosinophil levels in their blood and airways to reduce their corticosteroid dose. Eosinophils are a type of white blood cell involved with the production of interleukins. High eosinophil levels are directly linked to an increased risk of severe asthma.

Unlike the previous studies, dupilumab was shown to be effective regardless of patients’ eosinophil levels. Despite the reduced prednisone dose, patients in this study not only experienced a decrease in asthma exacerbations, but their lung function also improved significantly.

“Ultimately, our goal is to find new treatment pathways that allow us to circumvent the use of corticosteroids,” said Nair.

“Since dupilumab showed a significant improvement on asthma control regardless of eosinophil levels, we may be able to use this treatment for a wider range of patients than we previously thought possible. This might be due to the broad effects on inflammation in asthma of the two proteins that we were able to block with dupilumab. The treatment was not associated with any serious side effects.”

Learn more: Study Demonstrates New Treatment for Severe Asthma

 

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Could microRNA be a treatment for inflammatory diseases such as asthma and cancer?

via Wikipedia

A microRNA that regulates inflammation shows promise as a treatment for inflammatory diseases such as asthma and cancer, according to research published in Cell Reports.

The microRNA, known as miR-223, is highly expressed in blood cells that cause inflammation (neutrophils). When they’re working correctly, those blood cells help protect the human body against infections, but sometimes they damage host tissue instead of microbes, causing chronic inflammation and disease.

To uncover the link between miR-223 and inflammation, a Purdue University research team created a zebrafish totally deficient of miR-223. Then they cut off a small chunk of its fin.

“The inflammation was really robust,” said Qing Deng, a professor of biological sciences at Purdue and corresponding author of the paper. “Neutrophils accumulated at the wound and they just kept coming. This is consistent with the literature, but we wanted to understand why.”

Extensive gene expression analysis led them to pathway NF-kB, a protein complex found in nearly all animal cell types that regulates inflammation and cell proliferation. Heightened activation of this pathway is the cause of increased inflammation, although it’s limited to the deeper, or basal, layer of the epithelium. This means any therapeutics would need to reach the basal layer to work.

The same pathway plays an important role in human bronchial epithelial cells, which are critical in the development of asthma, according to the study. MiR-223 suppresses the pathway, which means supplementing it to epithelial cells could help control inflammatory disease.

“We don’t have human trials yet, but we think it’s promising,” Deng said. “Instead of using steroids to drive away the immune cells, maybe this microRNA could be given.”

Learn more: MicroRNA could help treat cancer and asthma

 

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Is this the path to end allergic reactions?

Researchers have discovered a new approach for antibody-based treatment of allergy and asthma. It is nothing less than a breakthrough that could have a major impact on development of new medicine in years to come. The Photo shows Edzard Spillner (Photo: Lars Kruse)

Researchers have found a new mechanism in which an antibody can prevent allergic reactions in a broad range of patients. It is a scientific breakthrough, which could pave the way for a far more effective allergy medicine.

There was great excitement in the laboratory when researchers from Aarhus University recently discovered the unique mechanisms of an antibody that blocks the immune effect behind allergic reactions.

The team of researchers from the Departments of Engineering and Molecular Biology and Genetics together with German researchers from Marburg/Giessen has now described the molecular structure and mechanisms of action of the antibody, and the results are surprising.

They were hoping to find new methods to improve existing treatment, but instead they identified how a specific antibody is apparently able to completely inactivate the allergic processes.

The antibody interacts in a complex biochemical process in the human body by which it prevents the human allergy antibody (IgE) from attaching to cells, thus keeping all allergic symptoms from occurring.

“We can now describe the interaction of this antibody with its target and the conformational changes very accurately. This allows us to understand, how it interferes with the IgE and its specific receptors on the immune cells of the body, which are responsible for releasing histamine in an allergic reaction,” says Edzard Spillner, associate professor at the Department of Engineering, Aarhus University.

The research results have now been published in the prestigious scientific journal Nature Communications.

Allergic effects of birch pollen and insect venom eliminated
Generally, an allergic person produces high levels of IgE molecules against external allergens when exposed to them. These molecules circulate in the blood and are loaded onto the effector cells of the immune system which triggers the production of histamine and thereby an immediate allergic reaction in the body.

The function of the antibody is that it interferes with binding of IgE to the two specific effector (CD23 and FceRI) on the immune cells, thereby making it impossible for the allergy molecule to bind.

Furthermore, the researchers have observed that the antibody also removes the IgE molecules even after binding to its receptors.

“Once the IgE on immune cells can be eliminated, it doesn’t matter that the body produces millions of allergen-specific IgE molecules. When we can remove the trigger, the allergic reaction and symptoms will not occur,” says Edzard Spillner.

In the laboratory, it took only 15 minutes to disrupt the interaction between the allergy molecules and the immune cells.

The researchers have conducted ex vivo experiments with blood cells from patients allergic to birch pollen and insect venom. However, the method can be transferred to virtually all other allergies and asthma.

Hope for better medicine
Today, one in three Europeans suffer from allergic diseases, and the prevalence is steadily increasing. The treatment options are limited, but the researchers now expect that their scientific results will pave the way to developing completely new types of allergy medicine.

“We can now precisely map how the antibody prevents binding of IgE to its receptors. This allows us to envision completely new strategies for engineering medicine of the future, “says Nick Laursen, assistant professor at the Department of Molecular Biology and Genetics.

The antibody is particularly interesting because it is effective, and at the same time considerably smaller than therapeutic antibodies currently used to produce allergy medicine.

“It is a so called single domain antibody which easily produced in processes using only microorganisms. It is also extremely stable, and this provides new opportunities for how the antibody can be administered to patients,” says Edzard Spillner.

Unlike most therapeutic antibodies already available on the market, the new antibody does not necessarily have to be injected into the body. Because of its chemical structure it might be inhaled or swallowed, and these new consumption methods will make easy, cheap and much and more comfortable for the patients to handle.

However, before new allergy medicine can be produced the researchers will have to conduct a wide range of clinical trials to document the effect and safety of the antibody.

Learn more: New research can put an end to allergic reactions

 

 

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