Oxford researcher receives funding to study genetic mechanisms of rare forms of asthma

An Oxford researcher has been awarded funding to expand her cutting edge research into the genetic mechanisms of rare and severe forms of asthma.

Dr Anastasia Fries, NIHR Academic Clinical Fellow in Respiratory Medicine, was awarded a three-year MRC Clinical Research Training Fellowship worth almost £289,000 over the next three years.

Her project will entail conducting whole genome sequencing on 500 patients with severe asthma in Oxfordshire. To work out how novel genetic findings drive asthma, the team will use an innovative approach using stem cells to grow lung tissue in the lab. 

The project arose from a single patient in the Oxford severe asthma clinic, Sam Day, who had an unusual form of severe asthma that had not responded to standard treatments. The team, which is supported by the NIHR oxford Biomedical Research Centre (BRC), felt certain there was a genetic component to Sam's condition.

Sam, aged 33 from North Oxford, developed severe Crohn's disease as a child and had to undergo a series of major procedures, including an ileostomy, bowel resection and removal of her colon. She says: "I was unwell for a number of years, and then things settled when I was about 19 and I was able to go back to college. I worked at the John Radcliffe and Churchill hospitals as a nursing assistant, which I loved. And then suddenly I started waking up breathless and I didn't know why."

After being admitted to hospital in 2019, Sam was found to have eosinophilic asthma. Normal treatments were ineffective and she has experienced a host of health problems, ranging from steroid-induced diabetes to muscle weakness resulting in a parastomal hernia. She is now on a drug, dupilumab, which has improved her life.

"I'll never be the same again, I'll never be able to do anything strenuous. I won't be able to do nursing again," Sam explains. "I'm having to get used to the new me. Life has changed completely, but it's so much better than it was before, and I'm so grateful.

"The Oxford team have been so supportive through it all, and when they said they were looking into the genetics of asthma, I was quite proud that something good has come out of something so terrible. It's not going to help me, because it's still in its infancy, but it will help other people."

The genetic sequencing carried out on Sam's samples revealed a new mutation which is affecting a cell pathway implicated in asthma, but the mutation is extremely rare and people would not normally be able to survive it. Now this approach is being expanded to look for other patients with severe asthma who might have rare genetic mutations.

Sam says: "As of now, I'm the only person in the world that is known to have this genetic mutation. I may be an anomaly, but that doesn't mean there won't be other people down the line. This also opens the door to tailoring treatment for specific genetic profiles - why does one treatment work for one person, and doesn't work for someone else with the same condition? So many people have asthma and so many people die from it unnecessarily, this gives us hope of understanding asthma better."

Anastasia's project has two main components: the first is using whole genome sequencing to find rare genetic variants in patients with severe asthma, and different sub-types of asthma to try and understand the mechanisms that are driving these different forms of the disease.

The second part of the project is to grow 'lung cells' derived from stem cells in the laboratory, edit the genes to reflect the mutations witnessed in patients and better understand their impact. Currently, to understand what causes the disease, scientists take biopsies from the lungs of patients with asthma. But the results are limited by the small number of cells that can be grown from these samples.

Growing from stem cells taken from a blood sample has the added advantage of being a much less invasive procedure for the patient.

"There's been a gap in asthma research in really understanding how genetic mutations work at a cellular level," Anastasia explains. "We are setting up a model where we can take stem cells - from a skin biopsy or blood - and reprogramme them into 'lung epithelial cells' and then grow that tissue in the lab.

"We can then use gene editing techniques to replicate mutations we've seen in the sequencing of the patients' cells. This will allow us to study their functional impacts in more detail - and hopefully identify variations in the DNA that are associated with specific sub-types of asthma."

Prof Timothy Hinks, Associate Professor of Respiratory Immunology at the University's Nuffield Dept of Medicine and Honorary Consultant at Oxford University Hospitals, said: "We know that asthma is partly caused by genetic risk factors, but these genetic causes have been difficult to study. While there has been progress in the past 10 years, with the recognition - and effective treatment - of a new sub-type of asthma known as eosinophilic asthma, we still do not fully understand what causes it, and still lack effective medicines for other forms of asthma.

"This is a timely and exciting area in asthma research, which has the potential to answer key questions about the causes of asthma and help patients with severe forms of this disease, which can be extremely difficult to treat. With this work, we are starting to approach asthma through an endotyping approach, that is, moving towards precision medicine where we can categorise patients into different sub-types of asthma."

Anastasia adds: "We expect to gain a richer and more detailed understanding of the genetic causes of asthma, particularly how genetic mutations cause changes in the cells of patients with asthma. This knowledge may in future allow us to identify new drug targets for these rare forms of asthma, as well as helping respiratory clinicians to predict which patients will respond best to specific treatments."

The project is being carried out in partnership with the healthcare company Sensyne Health.