- Home
- GSK in focus
- Cystic fibrosis: the vicious cycle
Cystic fibrosis: the vicious cycle
Cystic fibrosis (CF) is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator. That's the science. The reality for patients with this life-threatening disease can be hard. What is GSK doing to help them?
Cystic fibrosis facts
- Cystic fibrosis is the most common lethal autosomal recessive genetic disease among Caucasians.
- Over 8,000 patients in the UK suffer from CF, over 33,000 in the US and an estimated 100,000 globally. Each year, there are over 1,000 new diagnoses.
When Sophie Longton was a little girl, a school friend said to her: “I told my big sister that you’ve got cystic fibrosis and she said you’re going to die when you are 20 years old."
Today, Sophie has passed that 20-year mark, but she has no thoughts of dying. True, each day she takes no fewer than 50-60 different tablets, undergoes hours of rigorous physiotherapy and uses nebulisers to help clear mucous from her lungs. Yet since her friend's message, Sophie has won school cross-country races and awards for community achievement and fund raising, and gained a university degree.
No, Sophie is very much alive, but it's not been easy - nor is her daily routine. "I get through a box of tissues in a morning doing physiotherapy, sometimes more. I try to go running every day because that is my way of controlling things - it clears the mucous and reduces the potential for infection. I usually run for a good 30 minutes a day. I leave a trail of mucous behind me - and nobody ever wants to run behind me…"
She adds: "If you look at me, you might think I look really well. But despite the fact that my lung function is the best it’s been and I’m running every day, yesterday I was coughing up blood. I get frustrated - why is this happening when I’m supposed to be at the peak of health? It makes it hard for me to understand why things like that happen, but I just try and be positive."
Diagnosed at the age of eight - most children are much younger when the disease is identified - Sophie is an inspiring example of how life can be lived to the fullest possible by somebody shadowed by a life-threatening disease. “I believe in living life 100 per cent and I’m determined not to let CF stop me doing anything,” says Sophie.
Future therapies for cystic fibrosis
As Sophie's Longton’s regimen suggests, current therapies for cystic fibrosis are aimed at promoting mucous clearance, controlling infection and improving nutrition, but what of the future?
One person keeping close to developments is David Lipson, of GSK’s Respiratory CEDD, Discovery Medicine, who was the director of the Adult Cystic Fibrosis programme at a local university in Philadelphia before joining GSK in 2007.
David explains that CF is caused by a defective salt channel. A patient needs two gene mutations to inherit the disorder - a mutation that is in an ion channel gene which causes dysfunction of the salt channel and ion transport abnormalities. "It is these ion transport abnormalities that alter the airway secretions and start off a vicious cycle in patients with CF that causes infection, tissue damage and further inflammation," says David.
"This inflammation feeds off itself, primarily caused by neutrophils - white cells that fight infection then further alter airway secretions. This then leads to further infection, further tissue damage, and further inflammation, setting up the vicious cycle. The tissue damage then leads to bronchiectasis, lung damage, airflow obstruction, and eventually respiratory failure."
Survival in patients with CF has improved over the years, although there is still significant unmet need and the average life expectancy is about 37 years of age. "Primarily, patient survival has improved because of aggressive airway clearance, new antibiotics and our general understanding of CF. Unfortunately, though, we still have significant work to do."
Patient testing
Organ attack
Cystic fibrosis (CF) is a disease that affects many organs in the body. It is characterised by progressive airway obstruction, meaning difficulty in getting air out of the lungs.
It is also characterised by bronchiectasis - enlarged airways that get filled with mucous and inflammation - and pancreatic insufficiency. This means it is difficult for patients to absorb and digest food.
In CF, the body produces unusually thick and sticky mucous. This clogs the lungs and so can be life-threatening. It can require intravenous antibiotics as well as hospitalisation. Additionally, it may destroy the pancreas and prevent the natural release of enzymes from the pancreas which prevents the body from absorbing nutrition and fats.
Ruth Tal-Singer of GSK’s Respiratory CEDD Discovery Medicine, sets the background by picking up on the inflammatory ‘vicious cycle’ referred to by David.
"Patients with CF are colonised with bacteria from a very young age, so there is an overwhelming response of neutrophil infiltration into the lungs, which overcomes our natural anti-inflammatory defences," says Ruth.
"These activated neutrophils release DNA which causes thickened mucous to make it very difficult to clear bacteria and debris from the airways. Neutrophils also release enzymes including elastase that can cause lung damage."
Could something be done to inhibit this neutrophilic inflammation? Ruth points to a drug currently initiating clinical development in the GSK clinical pipeline, a CXCR2 antagonist which targets such inflammation.
Formally, this CXCR2 antagonist is a potent inhibitor of chemokine-induced neutrophil activation that targets the 'vicious cycle' created by neutrophils in the lungs. On the human level: "We're very excited by the fact that the compound is currently being tested in patients with CF - especially those of us who have worked in GSK for many years," says Ruth.
Whilst there are no guarantees of success, Sophie and other patients with this particularly unpleasant disease, not to mention their families and care-givers, will also be pleased.
