Developing innovative therapies to treat asthma

Michael Roth from University Hospital Basel & University Basel gives a compelling overview of research into asthma and need to develop innovative therapies to treat the disease

Asthma is the most frequent common, non-communicable chronic inflammatory airway disease, which is often misdiagnosed and therefore incorrectly treated, even in industrialised countries including the European Union (2016 Symposium of the EU on the Awareness of Allergies). The costs for asthma in 2016 were estimated at €19.6 billion in the EU; the costs include therapy and loss of productivity.

Asthma presents as a limitation of breathing capacity with reversible airflow obstruction, bronchospasm, cough, airway hyper-responsiveness, chest tightness, wheezing and chronic airway inflammation. The pathogenesis of asthma was assumed to result from chronic airway inflammation which leads to irreversible airway wall remodelling. New studies strongly suggest that both pathologies, inflammatiofn and remodelling, occur independently, but affect each other.

Clinical studies in adults and children provided evidence that airway wall remodelling is not the result of long-lasting chronic inflammation, instead, it occurs within days after an allergen challenge in sensitive adults. In childhood asthma, airway wall remodelling correlated with the frequency of wheezing episodes which did not show any sign of inflammation. Airway inflammation induced symptoms can be well controlled, while airway wall remodelling is resistant to all available therapies.

Despite decades of investigations, the pathogenesis of asthma is not well understood and therefore, the disease cannot be cured. In the 1920s, asthma was described as a disease characterised by increased airway smooth muscle cells and mucus accumulation in the airways. Later, immunological studies suggested that asthma is a disease caused by chronic inflammation of the airways.

Anti-Inflammatory Drugs

Consequently, anti-inflammatory glucocorticoids were investigated and applied in asthma therapy and combined with muscle relaxing drugs such as long-acting β2-agonists are the most prescribed therapies for asthma. Other anti-inflammatory drugs such as phosphodiesterase inhibitors, prostaglandin E analogues and anti-oxidant were added to asthma therapy. However, their anti-inflammatory effects were not sufficient to replace glucocorticoids.

The development of new asthma therapies is also limited by the availability of animal models, which do not reflect all pathologies of the human disease, rather than they present either the chronic inflammation or the remodelling but not both pathologies together. The reason for this incomplete presentation of human asthma pathologies in the models may be due to the natural living conditions of the animals. Most animal models use rats or mice, which have a different airway structure compared to humans. Taking into account that the natural habitat of these rodents is dusty and loaded with allergens makes it unlikely that they would be susceptible to develop inflammatory airway diseases such as asthma.

In the past decades, humanised antibodies to specific cytokines such as IL-3, IL-4, IL-5, IL-13 and TNF-α, have been developed as novel asthma therapies. However, they benefit only relative small sub-groups of patients with specific asthma phenotypes, which are difficult to identify by the available diagnostic methods. Neutralising the above-mentioned cytokines mainly benefits patients with eosinophilic asthma as demonstrated in several clinical studies; however, the contribution of eosinophils to the pathogenesis of asthma is not well understood. None of these cytokine-specific antibodies showed any effect on airway wall remodelling in humans.

One humanised monoclonal antibody application, neutralising circulating IgE, has been reported in several clinical studies to achieve lasting reduction of chronic airway inflammation in patients with allergic asthma. Neutralisation of circulating IgE in patients with allergic asthma resulted in a lasting reduction of asthma symptoms, even after the regular use of the IgE neutralising antibody was halted. It is suggested by several studies that neutralising IgE may be the only therapeutic strategy that also reduces airway wall remodelling.

However, this effect of neutralising IgE antibodies has not been proven by direct evidence in patients. There is also evidence that IgE neutralising antibodies may have unwanted side effects, but the data on this aspect is insufficient to draw conclusions. Furthermore, some new studies indicate that neutralising IgE does not benefit all patients with allergic asthma and the nature of the allergen to which the patient response may affect the efficacy of the drug.

Again, the application of humanised antibodies creates the necessity to develop new diagnostic tools enabling the classification of asthma patients. It should also be mentioned that humanised antibodies increased the costs of asthma therapy significantly. The need for more specific diagnosis of asthma phenotypes will further increase the overall costs of asthma therapy.

Vitamin C

Recently, there is new interest in the role of vitamins in the pathogenesis of chronic inflammatory lung diseases. Vitamin C deficiency during embryogenesis and childhood has been linked with an increased susceptibility to develop chronic inflammatory lung diseases later in life. It is not proven that vitamin C supplementation during adulthood has any beneficial effect on the prevention of asthma attacks. Similar results have been described for vitamin D and the B vitamins. Scientific proof of the crucial role of vitamins as a preventive factor for chronic lung inflammation is insufficient. This lack of information may be caused by a common disbelief that the deficiency of a specific vitamin increases the susceptibility to chronic inflammatory lung diseases.

The lack of therapies or drugs to target airway wall remodelling in asthma presents a major problem which was recognised in 2015 by the American Thoracic Society. However, the pharmaceutical industry does not have any drug in their pipelines which is focused on this aspect of asthma. Instead, new glucocorticoids or other anti-inflammatory drugs are under investigations. One of the major reasons that break through could not be achieved in finding effective new therapies targeting airway remodelling in asthma is because many innovative study proposals were rejected by funding organisation with the argument of not enough supporting data. The latter is of course due to insufficient funding. If this negative cycle cannot be broken, no innovative asthma therapies can be developed.

Please note: this is a commercial profile

Michael Roth

Research Group Leader,

Pulmonary Cell Research

University Hospital Basel & University Basel

Tel: +41 61 265 2227

Michael.roth@usb.ch

https://biomedizin.unibas.ch/nc/aboutus/people/profil/profile/person/roth-3