A potential new treatment for asthma that works by targeting the cause of the disease, rather than just masking its symptoms, has been revealed in a study published today in the Journal of Clinical Investigation Insight.
Preclinical findings show how a drug, currently well tolerated in clinical trials for cancer, is able to ‘switch off’ and reverse the uncontrolled inflammation responsible for driving and exacerbating asthma.
The research was led by Dr. Rhys Allan, Dr. Christine Keenan and Professor Stephen Nutt at the Walter and Eliza Hall Institute of Medical Research, along with collaborators at the University of Newcastle.
One in nine people in Australia have asthma and Melbourne has one of the highest incidences of the disease in the world.
Current asthma medicines such as airway relieving inhalers only serve to ease the symptoms of chest tightness, shortness of breath and coughing.
Anti-inflammatory steroids are associated with many side-effects.
And recent developments in targeted injectable therapies are very expensive.
Furthermore, none of these medicines cure the disease, so new and improved options are urgently needed.
A game-changer for asthma treatment
Dr. Keenan said the team’s research could dramatically improve the future of asthma treatment because they had identified a small molecule inhibitor, or drug, that could target the cause of disease, rather than just alleviating the symptoms.
Credit: Walter and Eliza Hall Institute of Medical Research
“I have been researching asthma in the preclinical setting for a long time and have never seen a treatment wipe out signs of an allergic immune response like this before. It’s exciting because these findings could be the stepping stone to developing an effective new treatment for allergic asthma,” she said.
Reversing asthma-causing inflammation
Asthma is a long-term lung condition that currently has no cure.
People with asthma react to environmental triggers such as pollen and dust mites. T
he uncontrolled inflammation associated with this allergic reaction restricts airways, increases mucus and makes it hard to breathe.
Dr. Allan said the researchers, who are experts in the epigenetic regulation of gene expression, set out to use their knowledge to target and arrest the cause of uncontrolled inflammation.
“Our early research identified that the enzyme Ezh2, which is an essential component of the epigenome, was critical to the immune system’s ability to drive inflammation in response to allergens.
This indicated that an Ezh2 inhibitor drug could effectively suppress inflammation in an allergic response,” he said.
Asthma is a chronic disease of the airways that causes reversible difficulty in breathing through bronchoconstriction, mucus hypersecretion and airway remodeling and afflicts over 300 million people worldwide [1,2].
Asthma is a heterogeneous disease that can be atopic or nonatopic, and demonstrates various subclinical phenotypes [3].
The variety in asthma phenotypes provides challenges to treatment as phenotyping asthma is neither easy nor readily affordable.
This may account for the failure of many drugs to proceed beyond early Phase II studies as patients are not adequately phenotyped [4].
Until better matching of phenotypes to driver pathways or molecules is achieved, phenotype-specific treatment using expensive biologicals for example will not be cost effective [5].
The adaptive immune response in asthma is regulated by CD4+ T-cell subsets.
The principle two subtypes of T helper cells are type 1 (Th1) and type 2 (Th2) which drive the cellular and humoral immune responses respectively [6].
Asthma is characterized at the cellular level by hyper-responsiveness of Th2 in both atopic (allergic) and nonatopic asthmatics [7,8].
In susceptible individuals, the Th2 response is stimulated by environmental effectors including allergens, temperature, humidity and air pollution [6].
This process of activation in allergic asthma begins with the airway epithelium, which upon stimulation releases factors which subsequently activate phagocytic cells and together they enable the activation of Th2 cells [6].
Th2 cells are able to self-propagate by the release of IL-4; drive infiltration of eosinophils by releasing IL-5 and activate B cells, which release antibodies against the allergens, by releasing IL-13 [6].
IL-13 also plays a major modulating role on airway epithelial cells increasing the production of mucins, periostin and other mediators [9].
Other T-cell subtypes also play a role in asthma, including the balance of the IL-17-producing Th17 cells and Treg.
Th17 cells are associated with neutrophilic inflammation [10] and have been shown to contribute to severe asthma and relative corticosteroid insensitivity [11].
By contrast, Treg cells are able to repress cytokine release and proliferation from other T-cell subtypes [12], including Th17 cells. The balance of Th17/Treg cells in peripheral blood of asthmatics is skewed toward Th17 [13,14] which inhibits the resolution of inflammation and increases neutrophilic infiltration.
Generally asthma is well controlled by inhaled corticosteroids and bronchodilators; however, 10% of patients suffer from ‘severe’ asthma that is poorly controlled even by high doses of inhaled and oral steroids and other treatments such as theophylline, anti-IgE or leukotriene receptor agonists [5].
While asthma can be controlled it cannot be cured, therefore the development of new treatments and identification of novel drug targets are a priority in asthma research.
Asthma has been shown to have a heritable component in large twin studies [15], and by using polygenic heritability estimates [16].
A heritable phenotype can be the product of many different mechanisms; these can be divided into two categories: those that change the DNA sequence and those that do not.
To date much of the research into the heritability of asthma has focused on the changes to the DNA sequence, however large-scale genome-wide association studies (GWAS) have only identified a handful of genetic changes or SNPs linked to asthma which are highly significant on a population scale but not predictive at the individual level [17,18].
It is also unknown whether these changes are causative and it is likely that causality will be linked to different environmental exposures in selected subphenotypes of asthma.
Research is therefore becoming more focused on heritable characteristics that are not due to altered DNA, termed epigenetic modifications, and the sum of these modifications termed the epigenome.
These epigenetic processes include modifications to DNA-binding histones, applying methylation marks to cysteine in DNA and noncoding RNAs such as miRNA [19].
To date studies of the epigenome in asthmatics have demonstrated changes in monocytic DNA methylation [20] and histone modification [21], blood leukocyte [22] and eosinophil [23] methylation, CD4+ T-cell histone modifications [24–26] and smooth muscle and T-cell miRNA expression [27,28] and histone acetylation at distinct residues [29] compared with their healthy controls. What these data are unable to show is whether these changes cause, or are a result of, asthma although animal models may help resolve this issue.
Various techniques have been developed to investigate epigenetic regulation of gene expression.
These include using methods such as chromatin immunoprecipitation (ChIP) to confirm specific histone modifications at single gene promoters or at a genome-wide level, or to map the location of specific histone modifications with chromatin structure (using ChIP-Seq [24] and DNase 1 hypersensitivity [30]), measuring DNA methylation (bisulfite sequencing using array or next-generation sequencing [31]) and expression profiles of noncoding RNA (gene array or PCR-based analysis [32]).
There is growing number of available tools which can alter the extent to which cells modify histones and methylate DNA which means we can begin to investigate the role of epigenetic modifications in asthma and identify potential new therapeutics.
It is important to note that each cell type has a distinct epigenome and it is important to examine changes with disease in single cell types [33] or to use bioinformatic tools to deconvolute data to allocate to single cells [23].
The encyclopedia of DNA elements (ENCODE [34]) a project to catalog the regulatory elements in human cells and its follow-up of the Epigenome Roadmap [35] are two projects that have built reference epigenomes for 127 tissue and cell types [36,37].
The Epigenome Roadmap has been able to gather reference epigenomes for a variety of T-cell subtypes and B cells and this information is ripe for analysis if compared with more asthmatic samples.
Through a series of laboratory studies the researchers showed that the inhibition of Ezh2 could dampen the overreaction by immune T cells that lead to uncontrolled inflammation in the lungs, as well as reverse any established inflammation associated with asthma.
“Interestingly, the Ezh2 inhibitor used in our study is currently in clinical trials for blood cancer,” Dr. Allan said.
“Because the drug is already well tolerated in humans, it’s reasonable to expect that the transition from oncology to treatments for inflammation should be smooth.
We hope that this study illuminates the way forward for further investigation into a highly targeted and effective medicine for asthma,” he said.
More information: Christine R. Keenan et al. Polycomb repressive complex 2 is a critical mediator of allergic inflammation, JCI Insight(2019). DOI: 10.1172/jci.insight.127745
Provided by Walter and Eliza Hall Institute of Medical Research
