Published: 10 August 2022
The potential for gene therapy in cystic fibrosis
A single faulty gene is responsible for causing cystic fibrosis – an inherited, life-limiting condition affecting more than 10,500 people around the UK. The affected gene, known as CFTR, causes the body to produce a thick mucus that particularly affects how the lungs and digestive system work.
People with cystic fibrosis are more vulnerable to recurrent lung infections that damage and eventually destroy the lungs. Its treatment includes management of patients’ symptoms, such as antibiotics and physical clearance of mucus. More recently, modulator drugs that directly target the basic defect (the proteins made by the faulty CFTR gene) have also become standard therapy, although they are not universally appropriate for all patients.
Following identification of the faulty CFTR gene in 1989, researchers began investigating whether gene therapy could deliver the correct gene directly to lung cells. This approach was intended to help the cells work normally and reduce the amount of mucus produced. Although more than 2,000 gene faults are known to cause cystic fibrosis, gene therapy is likely to be suitable for all patients.
Two main methods of delivering a correct copy of the gene have been tested: viral and non-viral vectors. Delivering the CFTR gene within deactivated viruses (viral vectors) is an effective method as some viruses’ natural properties allow them to enter lung cells. However, repeated treatments can fail because the body’s immune system recognises and destroys the viral vector, so the effects of treatment are short-lived. The alternative, non-viral vectors are a combination of the CFTR gene packaged inside a fatty coating (a liposome), which can also enter lung cells but trigger a lesser immune response.
Funded by a £3.2 million grant from the NIHR and the Medical Research Council (MRC) through the Efficacy and Mechanism Evaluation (EME) Programme, the UK Cystic Fibrosis Gene Therapy Consortium investigated whether this non-viral gene therapy for cystic fibrosis could safely improve patients’ symptoms.
The UK Cystic Fibrosis Gene Therapy Consortium brings together around 50 clinicians and researchers from the Universities of Oxford and Edinburgh and Imperial College London, with the goal of making gene therapy available for people with cystic fibrosis.
The consortium is led by Eric Alton, Professor of Gene Therapy and Respiratory Medicine at Imperial College London, who said:
Through our research, the consortium hopes to achieve a step change in the treatment of cystic fibrosis that focuses on replacing the function of the faulty gene and that is applicable to all people with cystic fibrosis.
- Professor Eric Alton, lead researcher
Evidence that gene therapy improves symptoms
The consortium’s earlier research had shown that in small studies of people with cystic fibrosis, inhaling a fine mist of liposomes carrying the correct CFTR gene allowed the gene to work for up to several weeks following each administration. As a founder member of the consortium and researcher with the EME project, Professor Deborah Gill explained the purpose of their study, saying: “By giving the therapy repeatedly over a whole year, we had the best chance of achieving clinical benefit in patients.” She continued:
Our study was a worldwide first in terms of the length of the study, the number of patients involved and the number of doses of gene therapy.
- Deborah Gill, Professor of Gene Medicine at the University of Oxford
Supported by the NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust, the NIHR Imperial Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London and the Edinburgh Clinical Research Facility, 136 patients with cystic fibrosis aged 12 years and over were recruited across the UK.
Dr Chris Boyd, Reader in Gene Therapy at the University of Edinburgh, and researcher with the project, noted that: “Inclusion of the Western General Hospital as a second trial site allowed us to recruit and treat a substantial proportion of the trial patients from across Scotland and the north of England, who were otherwise unable or unwilling to travel to London for treatment.”
Patients and carers of those with cystic fibrosis were closely involved in developing the study, ensuring it remained patient focused throughout. Their input helped shape its design and influenced important decisions, such as treatment length, to accommodate younger participants. All participants were randomly assigned to receive either a monthly dose of inhaled gene therapy or saline (placebo) for 1 year.
After 12 doses, some participants in the gene therapy group showed a significant stabilisation of their lung function compared with the decline seen in the placebo group. Those with the worst lung function saw the biggest improvements and there were no important side effects from treatment overall.
For the first time, this study confirmed that CFTR gene therapy could safely improve lung disease in cystic fibrosis and was suitable for repeated treatments. Their results were published in the Lancet Respiratory Medicine.
Commenting on the results, Professor Alton said: "Whilst the effect was inconsistent, with some patients responding better than others, the results were encouraging. This small benefit in lung function proved the concept that repeated administration of gene replacement therapy is a promising approach. However, a more efficient gene delivery system was needed to achieve greater and longer-lasting improvements in lung function.”
Supporting new gene therapy approaches
The evidence from this study paved the way for the consortium’s next steps in cystic fibrosis gene therapy research. With additional support from the MRC, the consortium developed a new inhaled viral vector, based on a novel lentivirus. Data from the EME study were used during its development as a benchmark to assess how effective and safe the lentivirus was. Published in the journal Thorax, the lentiviral vector was found to deliver the CFTR gene more effectively than the liposome vector in preclinical studies. It could also (uniquely for a viral vector) be used to treat patients multiple times as it evades the body’s immune response.
Supported by the data from the EME study and its development of the lentiviral vector, the consortium secured funding and partnership with the global pharmaceutical company Boehringer Ingelheim and the viral vector manufacturing specialists Oxford BioMedica. In a key step towards establishing gene therapy as routine clinical practice for patients with cystic fibrosis, the partnership combines expertise and resources to continue the development of gene therapy. The partners are currently planning the first clinical trials of the lentiviral vector in people.
David Ramsden, Chief Executive of the Cystic Fibrosis Trust said: “The partnership brings hope to the whole cystic fibrosis community and in particular to those who don’t benefit from the currently available medicines. All of those who have helped us to invest long term in the work of the UK Cystic Fibrosis Gene Therapy Consortium should be proud of helping to make this important step possible.”
The team went on to receive additional £6.4 million funding from the Wellcome Trust to further develop gene therapies using this novel lentivirus platform for five other health conditions.
Professor Alton explained how the potential impact of widely available gene therapy for cystic fibrosis patients cannot be understated, saying: The EME trial demonstrated that giving repeated gene therapy led to patients’ lungs getting better and led to new approaches to improve delivery of gene therapy.
Eventually we hope gene therapy will push cystic fibrosis patients towards a normal life expectancy and improve their quality of life significantly.
- Professor Eric Alton
The study was funded by the NIHR and the Medical Research Council through the Efficacy and Mechanism Evaluation (EME) Programme.
More information about the study is available on the NIHR’s Funding & Awards website.