Despite remarkable advances over the past years, the unmet needs in respiratory disease remain enormous. This is particularly true in progressive diseases such as Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF), with COPD being ranked as the third most common cause of death in developed countries. These diseases involve profound structural changes in the lungs, and current therapies do not address the underlying disease mechanisms. At AstraZeneca, our ambition is to increase our understanding of these drivers to enable the development of disease modifying treatments and potentially even cures.
A critical feature of both COPD and IPF is loss of normal tissue repair mechanisms with a failure of local stem cell function. To make a real difference to patients there is therefore a need to develop approaches that enhance lung repair to regenerate normal lung tissue. The first step on our journey is to get a much better understanding of these complex mechanisms and to define specific patient endotypes.
A recent area of research with significant importance to both COPD and IPF is cell ageing and senescence, and one of the leading experts in this field is Professor Peter Barnes at Imperial College London. To ensure AstraZeneca taps into the latest advancements and science, Professor Barnes was recently appointed as an Advisory Chief Scientist in the Respiratory research team at AstraZeneca to advise in this area.
Maria: “Peter, could you explain why this area of research has such importance in Chronic Lung Disease?”
Peter: “This is a very exciting time for drug discovery in lung diseases. We have seen enormous changes in the development of new drugs for severe asthma. Now the time has come to also explore the potential to develop better treatments for COPD and IPF that address the underlying progressive disease mechanisms and may eventually reverse the pathology. Focussing on regeneration and repair seems to be a very forward-thinking strategy which is also relevant to many other chronic diseases. Cellular senescence may be a critical feature of chronic lung diseases, as it particularly affects progenitor/stem cells to prevent tissue repair.”
Maria: “In what way could your recent work on cellular senescence in COPD inform the drug discovery process in this area?”
Peter: “There is increasing evidence that COPD involves accelerated lung ageing, with the accumulation of senescent cells in the lungs and that this may be linked to a loss of endogenous anti-ageing molecules. Oxidative stress is a major driving mechanism in COPD linked to cigarette smoking and environmental pollution. Therefore, we are assessing the impact of oxidative stress pathways on cell ageing and cellular senescence, to determine if targeting this is a viable therapeutic approach for these patients. More evidence implicating cellular senescence as a disease driver comes from studies in mice showing that deleting senescent cells extends lifespan by preventing age-related diseases. This can be achieved with so called senolytic drugs that selectively reduce viability in senescent cells by inducing apoptosis, without affecting normal cells.
Recent research shows that senescent cells spread senescence to other cells and that this effect increases with age. This could mean that elimination of senescent cells may stop this progression.
So, in summary, my answer to your question about the implications for drug discovery is that current treatments reduce symptoms and exacerbations, but not the underlying disease mechanisms so we need to search for drugs that target these mechanisms in a safe and effective way. Most likely, the effect would be greater in early disease which means early diagnosis also plays a significant role.”
Maria: “How does this impact on other approaches such as development of anti-inflammatory therapies for chronic lung disease?”
Peter: “Senescent cells release many inflammatory proteins that cause a low-grade steroid-resistant inflammation, with exactly the same pattern that we see in COPD, for example. Previous approaches to developing anti-inflammatory treatments for COPD have been disappointing as they may have been too specific. Targeting senescence may be a more effective approach.”
Maria: “Although your work has been mainly in COPD, does this have implications for other chronic lung disease and other diseases of ageing?”
Peter: “IPF is also characterised by cellular senescence and recent studies in mice with senolytic therapies showing efficacy in experimental lung fibrosis. Senescence is also a feature of other chronic diseases, so new drugs may have a broad indication and may also address the comorbidities that are commonly seen in COPD.”
Maria: “I believe we can make significant advances for patients with chronic lung disease. AstraZeneca has a bold ambition in this field, which will only be realised by multi-disciplinary collaboration in these complex diseases, and we are excited to have you working with us to help solve some of these challenges.”
1. Barnes PJ. Senescence in COPD and its comorbidities. Annu Rev Physiol 2017; 79: 517-539
2. Baker J, Vuppusetty C, Colley T, Papaioannou A, Fenwick P, Donnelly L, Ito K, Barnes PJ. Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells. Scientific reports 2016; 6: 35871.
3. Baker J, Vuppusetty C, Colley T, Hassibi S, Fenwick PS, Donnelly Le, Ito K, Barnes PJ. MicroRNA-570 is a novel regulator of cellular senescence and inflammaging FASEB J 2018.