This gene defect means the protein it produces, also called CFTR, is absent or does not function correctly. This disturbs the salt balance in most tubes within the body, including in the airways, gut and the reproductive system.
What does the gene mutation do?
Scientists have identified more than 2,000 different mutations in the CFTR gene. These mutations can be separated into six different classes that affect how the CFTR protein is produced or functions, and how it affects health.
The CFTR protein is an ion channel that controls salt and water balance. Although many organs in the body are impacted, people with CF are mostly affected by lung disease. The absent or poorly functioning CFTR protein causes the airway to become dehydrated. This results in production of thick sticky mucus that is hard to clear.
The mucus is a perfect breeding ground for bacteria, fungi and viruses. The resulting cycle of infection and inflammation slowly destroys the lung tissue.
Lung function in people with CF gradually and continually worsens, reducing their quality of life and causing early death for many.
Seventy years ago, the average life expectancy of a person born with cystic fibrosis was less than one year. Improvements in care have greatly improved survival to around 40 years. These include early detection, better nutrition and enzymes to aid digestion, as well as intensive daily physiotherapy, antibiotics and other drugs to treat lung disease. There is still no cure.
CF has almost become a hidden disease. You may not realise an acquaintance or co-worker has CF until the disease becomes well established and their quality of life deteriorates.
How is CF lung disease treated?
CF lung disease cannot currently be cured. Instead, most treatment approaches try to minimise symptoms and slow the progression of lung disease.
One example is twice-daily treatment with inhaled hypertonic saline (salty water). This has been used for more than a decade to treat CF lung disease by drawing water onto the airway surface, rehydrating the mucus, and allowing it to clear. Others include daily physiotherapy, which helps to clear mucus, and antibiotics, which treat bacterial infections.
Although CF treatments have improved dramatically over the last decades, most are designed to address the symptoms rather than the cause – the defective CFTR gene present in the cells.
When a person with CF nears the point of lung failure, a lung transplant becomes the only life-saving option. However, suitable donor lungs for transplant are rare and recipients must take daily medications to suppress their immune system so their bodies do not reject the implanted organ. This often produces substantial side-effects, and complications are inevitable.
Currently, the five-year survival rate of CF patients following double lung transplant is around 66%.
The disease creates a heavy physical and emotional cost to patients and their families, as well as substantial financial cost to the health system and more recently the Pharmaceutical Benefits Scheme (PBS).
What are genetically focused medicines?
Genetically focused medicines are a component of personalised medicine, in which a diagnostic test to determine a patient’s genetic makeup is used to select an appropriate therapy. Such medicines are beginning to show their real potential for treating CF.
Two new mutation-focused pharmaceuticals are now available. Kalydeco, a drug that improves the defective CFTR protein function, is available on the PBS for the 4% of CF patients with the G551D CFTR mutation. But it’s expensive, currently costing the Australian government A$174.5 million over four years (about $300,000 per patient each year).
The other mutation-focused pharmaceutical is Orkambi, a treatment for about 70% of CF patients (those with the F508del CFTR mutation). In April 2016, the Pharmaceutical Benefits Advisory Commission rejected Orkambi on the basis that the A$100 million annual cost was not accompanied by a demonstrated substantial benefit.
Similar rejections of Orkambi have occurred in Ireland and the United Kingdom; Canada has delayed its decision.
Other mutation-specific drugs that restore CFTR function are in development and in clinical trials. But it’s unclear whether they will be made available to patients through the PBS.
What is airway gene therapy?
Another particularly attractive genetically-focused option is gene therapy. This is designed to treat the cause, not the symptoms, of the disease. Airway gene therapy works by delivering a correct copy of the CFTR gene into airway cells to rectify the salt imbalance and improve lung health.
CF is potentially a good target for gene therapies because we probably only need to correct the CFTR gene, unlike cancer in which many genes are implicated and not all are known. The lung is also a relatively accessible organ for delivery.
A recent clinical trial in the UK showed that gene therapy was effective for CF lung disease. Monthly deliveries of the CFTR gene inhaled into the airways in small “fatty” globules called liposomes briefly stabilised the decline in lung health in some patients.
A far more efficient method of gene therapy delivery is under development which uses a highly modified and harmless virus as the vehicle that carries in the CFTR gene.
Some viral vectors (carriers) are capable of targeting airway stem cells, the specialised cells of the airway that constantly repair and replenish the cells of the lung. If stem cells are treated, patients might expect lasting benefit as their bodies automatically pass on the correctly functioning CFTR gene to their “daughter” cells.
Such treatment offers hope for lifetime or very long-lived benefits after a single set of treatments.
Importantly, an airway gene therapy of this nature would provide benefits regardless of a person’s CF mutation.
Pre-clinical studies look promising, but clinical trials of this method have not yet begun. The UK CF Gene Therapy Consortium is preparing for a trial in patients, but the effectiveness and cost are not currently known.
Genetic medicines will undoubtedly be the medicines of our future. But the emergence of effective, potentially curative, but often extraordinarily expensive genetically focused treatments is driving new debate about the cost versus benefit for CF and other diseases, and how these should be funded.
Martin Donnelley receives funding from the NHMRC, Women's and Children's Hospital Foundation, Cure4CF Foundation and Australian Synchrotron.
David Parsons receives research funding from the NHMRC, Cure4CF Foundation SA, the USA CF Foundation, and the Australian Synchrotron.
Authors: Martin Donnelley, Affiliate Senior Lecturer, University of Adelaide