Written by:
Ken Grime
Executive Director and Head of Bioscience, COPD & IPF, Early Respiratory and Immunology, AstraZeneca
What is idiopathic pulmonary fibrosis?
Idiopathic pulmonary fibrosis, or IPF for short, is a chronic and usually fatal lung disease in which the lungs become scarred and breathing becomes progressively more difficult. With an average survival of around three years following diagnosis, this is worse than some cancers.
Currently there are two treatments approved to slow down disease progression but nothing which can stop or reverse the lung scarring and the only potential option for cure is a full lung transplant.
The exact mechanisms involved in the pathogenesis of IPF are unclear and patients vary in their speed of deterioration, where the disease will progress rapidly in some and more slowly in others. However, it is difficult to predict how a patient’s condition will develop, as there appears to be limited genetic differences between the two groups. Additionally, some patients appear to be more susceptible to exacerbations and therefore, with rapid loss of a substantial proportion of their lung function, even one or two exacerbations can be fatal.
Discover our exciting emerging science behind idiopathic pulmonary fibrosis in the below video:
Research focus areas in idiopathic pulmonary fibrosis
We are committed to digging deep into the underlying biology of IPF. Critically we are targeting mechanisms like inflammatory macrophage activation, accumulation of fibrosis driving fibroblasts and ineffective rebuilding of the damaged lung epithelium. By addressing underlying disease drivers as opposed to the downstream symptoms we aim to prevent the progression of the disease, stopping fibrosis in its tracks and promoting tissue regeneration in the lung.
Targeting fibrotic pathways
Multiple mechanisms have been identified by our scientists which cause fibrosis, yet still more remain to be uncovered. One such example is the Wnt (pronounced wint) signal transduction pathway. This pathway plays a key role in activating stem-like cells to repair damaged epithelia and activation of fibroblasts which releases collagen, as part of the tissue damage response. In IPF, the Wnt pathway is upregulated and could be a potential target for novel treatment approaches1. Suppression could modify disease processes by slowing or preventing fibrosis both in IPF and other fibrotic diseases.
Promoting tissue regeneration
Lung epithelial cells exposed to chronic stress can become damaged and yet still remain resistant to cell death and clearance from the lung – a state known as senescence. As these cells continue to survive, they release signalling molecules to surrounding cells which promote further inflammation, fibrosis and consequently more cell damage, leading to chronic disease.
Markers can be detected within IPF lung tissue samples that are linked to senescence and removal of these senescent cells has been shown to restore pulmonary health in pre-clinical models2. By focusing our drug discovery research across different disease drivers, we can reasonably expect to reduce the burden of disease for IPF patients.
Avoiding the damage that leads to fibrosis
One factor that may contribute to lung fibrosis, according to genetic analysis of people with IPF, is instability in structures called telomeres. Telomeres cap the end of chromosomes and protect the DNA from becoming damaged. Without functioning telomeres, stem-like cells are unable to repair damage and this seems to be linked to fibrosis in some particularly aggressive forms of IPF. Recent collaborative work shows that lung fibrosis is particularly linked to telomere disruption in alveolar type II (ATII) cells. These stem-like cells specifically repair the lung air sacs where gases from the air move into and out of the blood3.
Leveraging technology in IPF research
To support our emerging research and assess our drug candidates, we have developed multi-cell in vitro models of human alveoli, known as organoids. These 3D cell cultures help to mimic the complex cell interactions in the lung and provide many advantages compared to simpler models, such as monocultures (one cell type) and 2D models (flat models).
AstraZeneca lung organoid used for IPF and COPD research
By combining our rich datasets with external data sources, we can leverage AI and machine learning to develop biomedical knowledge graphs. Knowledge graphs are networks of contextualised scientific data facts such as genes, proteins, diseases and compounds, and how they relate to each other. Since 2019, we have been working with BenevolentAI and have identified three novel targets in IPF which have been brought forward into our pipeline as potential drug targets.
In addition, as part of a partnership with researchers at the Icahn School of Medicine at Mount Sinai, we used bioinformatics to analyse changes in cells caused by IPF. By comparing these changes to the drug signatures of various compounds we could determine potential new options to explore in IPF drug discovery. The results were recently validated in a collaborative study involving the National Jewish Health and Yale University supported by the National Institutes of Health.4
Looking forward to the future of IPF care
We remain committed to following the science in IPF, it is a challenging disease with little innovation to date to transform care for patients. Our ambition is to develop the next generation of novel treatments for this underserved population to halt and potentially even reverse fibrosis in the lung and revolutionise prognosis in this devastating disease.
