P4O2 (‘Precision medicine for more oxygen’) is a Dutch consortium that conducts research into improvements in the prevention and treatment of lung diseases. The consortium consists of about 30 parties, including university medical centers, companies, Long Alliantie Nederland and the Longfonds. At UMC Groningen, the focus is on COPD, say pulmonologists Prof. Dirk Jan Slebos and Dr Maarten van den Berge.
Van den Berge is involved in clinical and genetic studies of asthma and COPD at the UMCG. Slebos mainly works on clinical studies into new treatments for severe COPD. “Patients from all over the country come here,” he says. “As a result, we can bundle a lot of data in a database and conduct research into the development of COPD. For example, we see hundreds of people with very severe COPD at a relatively young age from all over the Netherlands every year. We are one of the few hospitals to perform a bronchoscopy with valves with which we close off the most sick part of the lungs. This allows the healthy part of the lungs to work better. We therefore have specific data for all these patients.”
Different syndromes
Within P4O2, more cohorts are followed in this way, including a covid cohort and the so-called PRIL cohort of people who do not yet have COPD, but who are at risk for it. “From Groningen, we contribute with our COPD cohort,” says Van den Berge. “There are many researchers and companies around the clinical cohorts who can contribute knowledge and expertise. For example about the use of the electronic nose or radiology. In addition, samples are taken that we can use for more basic research in, for example, epithelial cultures.”
Apart from a rare genetic form, the exact cause of COPD is not yet known. It is often associated with smoking, but the connection is not clear: the majority of all (ex-)smokers do not get COPD, but almost everyone of all COPD patients in the Netherlands has smoked. “There are also all kinds of different syndromes within COPD,” continues Slebos. “The disease can develop quickly and at a young age or slowly, one gets inflamed airways and the other the lung tissue disappears. Little is known about these differences. That is why we want to collect as many characteristics of patients as possible, both clinically and biologically. With this we want to learn more about the origin and course of the disease and all kinds of interactions between, for example, genetics, characteristics of lung tissue, blood values and functions of proteins. Thanks to the collaboration within P4O2, we can also compare our data with those of the Amsterdam researchers studying the PRIL cohort, i.e. people at risk for COPD. In this way we hope to be able to find relevant differences and perhaps indications for the development of COPD.”
Big data
Key questions for the research in the UMCG are who gets COPD and what kind of COPD develops in which patient. A lot of research has been done on this in recent years, but today researchers have access to big data and all kinds of large-scale research methods, such as genomics, proteomics and other -omics. “They provide many new possibilities for studying diseases,” says Van den Berge. “That is what we do within P4O2. It has never been done in this form in a large COPD cohort worldwide. Another plus is that we follow patients for a long time. We do not conduct intervention research, but follow a scientific observational cohort in which we map people in great detail. Not just people with mild or severe COPD, but healthy controls as well. We want to include almost 600 people: 250 with severe COPD, about 250 with mild disease and about 100 controls.”
All kinds of data are collected, such as spirometry data, lung volumes, blood gases, quality of life data from questionnaires, frequency of exacerbations, smoking history, comorbidity and CT data. In addition, there is material from blood, urine, sputum, epithelial brushes from nose and bronchi and biopsies. Participants are given an annual lung function test for five years and patients are also seen if exacerbation occurs.
Phenotyping
Research is also being conducted into phenotyping of lung diseases. Van den Berge: “When I did my PhD research at the beginning of this century, a lung disease such as asthma was still seen as one disease. We knew that a large part of the asthma patients were allergic, but another part was not. And it was known that eosinophil cells sometimes play a role in asthma. But phenotyping still had little clinical significance. With the advent of inhaled corticosteroids, we saw that this medication is not effective enough in some patients. Over the past 10 years we have learned a lot about the treatment of that group of patients, with targeted therapies with biologicals.”
Today, anti-IL5 treatment is taking place in people with eosinophil-severe asthma who are unresponsive to other treatments. That works very well and has been a turning point in the treatment of these patients. But in the first studies with anti-IL5, about 15 years ago, no phenotyping was done yet. The first results were therefore negative: there was no effect on lung function and on exacerbations. “With such outcomes, a pharmaceutical company can decide to stop further development of the drug,” says Van den Berge. “Fortunately, anti-IL5 has subsequently been specifically studied in people with eosinophil-severe asthma. It turned out to work well for them. But this does indicate the importance of phenotyping. That characterization is now continuing. With the -omics techniques we now have the opportunity to investigate which biological processes are active and which are not in which subgroups of patients. Pharmacists are also interested in this, in order to be able to develop increasingly more targeted medication.”
Microbiome
The inclusion of patients is progressing well. The results of the first analyzes are only expected in some time, but it has already been shown that certain aspects of the respiratory microbiome in COPD are different than in people without COPD: there appears to be less diversity in the bacterial population, which is unhealthy for the airways. “The diversity is probably a predictor of the risk of lung attacks in COPD,” says Van den Berge.
According to Slebos, it is quite a job to see all participating patients in the UMCG every year. The question is also whether 5 years of follow-up is sufficient. “Maybe we should extend that a bit, says Slebos, “but it’s very exciting what will come out in the future. I personally would find it interesting to look more closely at COPD within families. We regularly hear from patients that COPD runs in their families, while we cannot identify a clear genetic factor for this. We could look not only at patients, but also at their relatives. Perhaps we can learn a lot from that too. Maybe we can add this aspect to the project later on.”
P4O2 is part of the National Lung Research Program that was set up by the Netherlands Respiratory Society (NRS) together with, among others, lung associations, specialists, patients and companies. 14.5 million euros has been made available for P4O2 by the Top Sector Life Sciences & Health (Health~Holland).
‘Airway-on-a-chip’
At the UMCG, the departments of Pathology & Medical Biology and Pulmonary Diseases are involved in P4O2. Hundreds of COPD patients at various stages of disease severity will be extensively examined and characterized. Furthermore, cells from the lungs of COPD patients are cultured in the lab into an ‘airway-on-a-chip’ model, for research into, for example, the effects of early damage signals, environment and lifestyle on the repair of damage in the airway tissue of patients. COPD patients. This technique can also be used to functionally test new drug targets.