April 06, 2026 —
At the ELRIG March 2026 meeting, Professor Eric Alton of Imperial College London presented a comprehensive overview of the progress made in respiratory gene therapy, highlighting how a 25-year collaborative effort in the UK has advanced the field from early experimental concepts to clinical-stage therapies for cystic fibrosis (CF) and other rare lung diseases. The work, led by the UK Respiratory Gene Therapy Consortium, demonstrates how persistent translational research is gradually overcoming the unique biological barriers of the airway epithelium.
Cystic fibrosis remains the primary target of respiratory gene therapy. The disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which disrupt ion transport in epithelial cells and leads to thick mucus, chronic infections, and progressive lung damage. While small-molecule CFTR modulators have significantly improved outcomes for many patients, they do not work for all genetic variants and may not fully address persistent inflammation or long-term disease progression. As a result, gene therapy approaches that directly correct the underlying genetic defect remain an important therapeutic goal.
Professor Alton emphasized that the respiratory tract is inherently difficult to target for gene delivery. Therapeutic DNA must overcome multiple barriers, including mucus layers, mucociliary clearance, extracellular defenses, and intracellular degradation before reaching the nucleus of airway epithelial cells. These challenges are even greater in cystic fibrosis patients, where thickened mucus and chronic infection further restrict access to target cells.
To address these challenges, the UK Respiratory Gene Therapy Consortium—bringing together researchers from Imperial College London, the University of Oxford, and the University of Edinburgh—adopted a coordinated, collaborative development model. By sharing data, resources, and strategy, the consortium has been able to move potential therapies from early laboratory work toward clinical testing.
One of the consortium’s earliest translational platforms focused on non-viral gene delivery, using plasmid DNA packaged in lipid carriers. This approach was designed to allow repeated dosing, which is critical for chronic diseases such as cystic fibrosis. The program ultimately led to a Phase IIb multidose clinical trial, the largest gene therapy study conducted in CF at the time. Patients received monthly nebulized doses over one year in a double-blind, placebo-controlled study. While the treatment did not produce large improvements in lung function, the therapy stabilized lung function compared with the expected decline seen in the placebo group, providing proof of concept that repeated respiratory gene therapy can deliver measurable clinical benefit.
Building on these findings, the consortium developed a second platform using lentiviral vectors pseudotyped with Sendai virus envelope proteins, which enable efficient entry into airway epithelial cells. Unlike non-viral systems, this viral vector integrates into the host genome, potentially enabling long-term gene expression after a single administration. Preclinical studies have shown efficient gene transfer across multiple species and durable expression in mouse lungs for nearly two years following treatment.
Safety evaluations have also been encouraging. Animal studies have shown no significant inflammatory toxicity in the lungs and no increased cancer risk above background levels in long-term analyses. The vector has been successfully manufactured at clinical scale, and aerosol delivery studies suggest that a significant proportion of vector activity remains intact after nebulization.
Following roughly 15 years of development, the consortium initiated its first-in-human clinical trial of the lentiviral platform for cystic fibrosis in 2025, marking an important milestone for the field.
Beyond cystic fibrosis, respiratory gene therapy is also being explored for other severe lung diseases, including ultra-rare surfactant protein deficiencies in newborns, such as surfactant protein B deficiency. In preclinical models, lentiviral gene therapy restored survival in knockout mice to near-normal levels. To accelerate development of these therapies, the research team has established a spin-out company, AlveoGene.
Professor Alton concluded by noting that key questions remain, including the optimal delivery route, the predictive value of animal models for human lung disease, and how treatment costs will be supported within healthcare systems. Nevertheless, he emphasized that respiratory gene therapy has moved beyond theoretical possibility into a phase of genuine clinical promise, addressing one of the most challenging delivery problems in modern medicine.
