Genetics and stem cells

Gene therapy breakthrough for cystic fibrosis

"Cystic fibrosis hope as new gene therapy improves condition," The Daily Telegraph reports. Researchers have, for the first time, managed to successfully "smuggle" healthy copies of genes into the lungs of people with cystic fibrosis.

Cystic fibrosis is a genetic condition caused by a mutated gene called CFTR. The mutation causes the lungs and digestive system to become clogged up with sticky mucus.

The goal of gene therapy for cystic fibrosis is to replace the faulty CFTR gene with a working one.

Previous attempts of using a virus to deliver the working gene proved unsuccessful, as the lungs' defence system against infection stopped the virus from entering.

In this new study, the researchers tried a different approach – the gene was encased in a bubble of fat, which was then delivered to the lungs via a nebuliser.

When compared to placebo, the nebuliser-delivered approach showed a modest, but significant, improvement in lung function (3.7%).

A 3.7% improvement may not sound that impressive, but the exciting news is that the technique actually worked in a few of the study’s participants in the first place. It may be possible to enhance the technique in the future to boost lung function dramatically.

It is likely that larger and longer trials are now being planned. 

Where did the story come from?

The study was carried out by researchers from the University of Oxford, the University of Edinburgh, Imperial College London, the University of Edinburgh, Royal Brompton & Harefield NHS Foundation Trust, NHS Lothian, and other centres in the UK and US on behalf of the UK Cystic Fibrosis Gene Therapy Consortium. The trial took place in the Western General Hospital, Edinburgh and the Royal Brompton Hospital in London

It was funded by the Medical Research Council (MRC) and the National Institute for Health Research (NIHR) through the Efficacy and Mechanisms Evaluation (EME) programme, with additional funding from the Cystic Fibrosis Trust and Just Gene Therapy.

A number of the researchers have patents related to the gene therapy reported in the study and also declared links to pharmaceutical companies. The team state the "funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report".

The study was published in the peer-reviewed medical journal The Lancet on an open-access basis, so it is free to read online or download as a PDF.

This story was widely covered by UK media. Overall, the media reported the story accurately, but the limitations of the study were not fully explained.

BBC News published an important quote from one of the researchers involved in this study, Professor Eric Alton, of Imperial College London, who said: "The effect is modest and it is variable. It is not ready to go straight into the clinic yet."

What kind of research was this?

This was a randomised controlled trial (RCT) that aimed to assess the effectiveness of non-viral gene therapy compared with inactive placebo in people with cystic fibrosis. It was a phase 2b trial, meaning it was gathering information on effectiveness and safety, which will hopefully pave the way to larger phase 3 trials comparing the technique with existing treatments.

Cystic fibrosis is a genetic condition in which the lungs and digestive system become clogged with thick, sticky mucus. Symptoms of cystic fibrosis usually start in early childhood and include:

  • a persistent cough
  • recurring chest and lung infections
  • poor weight gain

An early sign is that an affected child's sweat is unusually salty, which can be noticeable when you kiss your child. However, most cases of cystic fibrosis in the UK are now identified through screening tests carried out early in life, before symptoms appear.

There is currently no cure for cystic fibrosis. Treatment options for cystic fibrosis include those that aim to control symptoms, such as physiotherapy (a range of exercises can clear mucus from the lungs) and bronchodilators (a type of medication that expands the airways, making it easier to breathe), and antibiotics to treat lung infections. In some cases, a lung transplant may eventually be required, if the lungs become extensively damaged.

Previous studies have tried to use viruses to deliver a functioning CFTR gene into the lungs, with limited success. This study used a non-virus based method to deliver the CFTR gene – encasing it in a bubble of fat – in the expectation this would be more successful.

RCTs are one of the best types of study design to determine whether a treatment is effective. Potential biases are reduced through randomisation. This study was also double blind, meaning that both patients and those assessing them were unaware of whether the person had received treatment or placebo.

What did the research involve?

A group of 140 people with cystic fibrosis were randomly assigned to either the gene treatment, which was given the name pGM169/GL67A (78 patients), or placebo (62 patients).

Patients received either 5ml of pGM169/GL67A (containing 13.3mg of plasmid DNA and 75mg of the GL67A lipid mixture), or 5ml of inactive saline (salt solution) through a nebuliser (a machine that converts the medicine to a mist, so it can be inhaled into the lungs).

Patients received either treatment or placebo at 28-day intervals (plus or minus 5 days) for 12 months. Patients in both groups also received an average of three courses of oral or intravenous antibiotics during the trial.

Patients recruited for this study were from 18 sites in the UK and were aged 12 years or older. Their lung function was measured using a standard test called forced expiratory volume in 1 second (FEV1). This measures the amount of air that can be forcibly exhaled in the first second after a maximal inspiration. To be included in the study, participants had to have an FEV1 of 50-90% of the normal level.

The main outcome of interest was the change in the percentage of predicted FEV1. Other outcomes examined were CT scans of the lungs, self-reported symptoms ratings and quality of life scores.

The main analysis was per-protocol. Per-protocol means that only people who took the medicine as planned were analysed. This excludes those who had dropped out for any reason. Intention to treat analysis is the more realistic scenario, as people might stop treatment in the real world. Per protocol analysis gives a good idea of whether the medicine works in those who took it as intended.

In this study, the per-protocol analysis included 116 people, 83% of those were randomised.

What were the basic results?

Researchers found that, overall, the treatment (pGM169/GL67A) significantly improved FEV1 by 3.7% compared with placebo at 12 months follow-up. This was described as a "modest" benefit to lung function and a statistically significant one.

The changes within each of the individual groups were an average reduction of 4.0% in the placebo group, compared with a 0.4% reduction in the pGM169/GL67A group. This means that lung function got a little worse in both groups over the year, but those in the placebo group deteriorated more. This led some headlines to report that the new drug was able to "stabilise" symptoms; that is, stopping them getting any worse, which was accurate.

There was no statistically significant difference between groups in adverse effects like fatigue and increased respiratory symptoms and flu-like symptoms. Overall, authors say that some patients responded to the new treatment better than the others.

Six serious adverse events, all in the pGM169/GL67A group, were recorded. But neither the Data Monitoring and Ethics Committee, nor the Trial Steering Committee involved in the research, regarded any serious adverse event as related to the study drug. One event was considered to be possibly related to a trial procedure (bronchoscopy).

How did the researchers interpret the results?

The researchers concluded that: "Although we are encouraged by the first demonstration of a significant beneficial effect in lung function compared with placebo associated with gene therapy in patients with cystic fibrosis, the mean difference was modest, only recorded in some individuals, and at the lower end of the range of results seen in clinical trials which result in changes in patient-related care."

They added: "Further improvements in efficacy and consistency of response to the current formulation, or its combination with CFTR potentiators, are needed before gene therapy is suitable for clinical practice."


This RCT showed that a new non-viral-based gene therapy for cystic fibrosis was able to produce "modest" benefits in lung function compared to a placebo. The treatments were given once a month for a year.

The study had many strengths, including its double-blind randomised design, recruiting adequate numbers to demonstrate real differences between groups, and using pre-specified outcomes and sub-analysis. This means we can be confident in the reliability of the findings presented.

Although the findings of this study are encouraging, there are always limitations.

These include:

  • This study was relatively small, recruiting just 140 patients. This is normal for a phase II trial, but large clinical trials are needed to fully assess the effects and safety of this treatment in development.
  • Patients recruited in this trial had to be clinically stable to be included. This means they might be at their optimum respiratory health at this stage. Therefore, we don’t know how the treatment would work in clinically unstable or very severe patient groups.

It is important to realise that both groups' lung function got worse over the year, so the treatment as it stands is quite limited. The new gene therapy was able to lessen some of the deterioration, but not in all. Nonetheless, this gives the researchers hope and scope to work out how to improve it.

Optimising the dose, working out why it worked in some people and not others, and trialling the therapy in more people are the natural next steps in this treatment development.

This is very much a proof-of-concept study rather than a study that provides a viable treatment in itself. It is a breakthrough in the development of gene therapy treatment for cystic fibrosis, but there is a lot of refinement and experimentation needed before this could be a routinely available treatment.

NHS Attribution