Clinical trials begin for a first-in-class, inhaled gene therapy for people with cystic fibrosis

The LENTICLAIR 1 trial, which will evaluate the safety, tolerability and efficacy of the treatment, is being conducted by biopharmaceutical company Boehringer Ingelheim in partnership with the UK Respiratory Gene Therapy Consortium, including Radcliffe Department of Medicine researchers, and OXB (formally Oxford Biomedica).

Cystic fibrosis (CF) is caused by defects in the CFTR gene, which causes a build-up of thick sticky mucus in the lungs and digestive system. It causes lung infections and gradually affects the ability to breathe. The new lentiviral vector-based gene therapy works by inserting a functioning copy of the CFTR gene in the DNA of the epithelial cells in a patient's airway.

At present, some people with CF respond well to relatively new treatments known as CFTR modulator medicines, which work by targeting the related CFTR protein. However, these are not an option for around 10-15% of patients.

New treatment aims to improve lung function and reduce flare-ups

The aim of the new treatment being trialled, known as BI 3720931, is to improve lung function and reduce exacerbations (flare-ups, often leading to hospitalisation), for people with CF irrespective of their mutation type – including those who genetically cannot benefit from other CF therapies.

Around 36 men and women with cystic fibrosis will be treated at centres in the UK, France, Italy, Netherlands and Spain.

Cystic fibrosis is an inherited lifelong disease that gets worse over time. It is estimated to affect 105,000 people worldwide. There are more than 2,000 known mutations in the CFTR gene, which lead to different levels of the severity of the disease.

Lentiviral vectors are a type of gene therapy that exploit the ability of lentiviruses to infect human cells. Lentiviruses are a family of viruses that infect by inserting their genetic material into their host cell's genome. By modifying lentiviruses, scientists have been able to use them as a vehicle to insert beneficial genes into cells.

RDM Professors Deborah Gill and Stephen Hyde are members of the UK Respiratory Gene Therapy Consortium and were involved in the early development of the gene therapy product for cystic fibrosis lung disease. Professor Gill said: 'It is an exciting time to be involved in the field of gene therapy and we must do everything we can to accelerate the process and work to fulfil the promise of new treatments for genetic diseases.'

Professor Eric Alton, Professor of Gene Therapy and Respiratory Medicine at Imperial College London is leading the international trial. Professor Alton said: 'The UK CF Gene Therapy Consortium is very excited to have reached this milestone after 24 years of focused effort and in close collaboration with our funding partners. While the immediate target are those patients who are not eligible for CFTR modulators, this novel therapy has the potential to achieve long-lasting CFTR function improvement and disease modification for people with CF irrespective of their mutation type and importantly has the potential for re-dosing if needed.'

UK Respiratory Gene Therapy Consortium comprises researchers from Imperial College and the Universities of Oxford and Edinburgh. They have worked together for the last 25 years to progress gene therapy for cystic fibrosis.

In the first phase of the trial, different doses of the treatment will be given to evaluate safety, tolerability and select doses for Phase II. In the second phase, two selected doses or placebo will be given in a randomised, double-blind placebo-controlled dose expansion study to assess clinical efficacy and safety. After completion of the 24-week trial period, trial participants will take part in a long-term follow-up study, LENTICLAIR-ON.

The trial is expected to be completed in early 2027. Additional information about the trial is available via ClinicalTrials.gov at NCT06515002.