Radcliffe Department of Medicine, Annual Symposium, Oxford, 2016
For the first time, gene therapy for cystic fibrosis (CF) has had a beneficial effect on lung function. Plasmid engineering, the optimisation of the gene therapy formulation and toxicology studies in mice and sheep supported progression to clinical trials in CF patients. The formulation, which is aerosolised to the lungs, is composed of cationic liposomes complexed with a plasmid that is completely free of CpG dinucleotides and directs persistent high-level expression of codon-optimised CFTR under the control of the hCEFI promoter/enhancer (Hyde et al 2008 Nature Biotechnology 26: 549-551).
A Phase 1/2a dose escalation trial in 35 CF patients identified a safe (5ml) aerosol dose delivered to the lungs via a Trudell AeroEclipseII nebuliser. Subsequently, in a randomised, double-blind, placebo-controlled Phase 2b study, CF patients were given 12 aerosol doses at monthly (28±5 day) intervals.
The patients started the trial with an FEV1 % predicted lung function of between 50 and 90%, which was measured every month and at the end of the trial. They received 5ml of either nebulised plasmid‑liposome complexes (Active; n=64) or 0·9% saline (Placebo; n= 52) every 28 days. A significant treatment effect was observed in the Active group versus Placebo after 12 months, based on the primary outcome measure (FEV1; 3·7%, 95% CI 0·1–7·3; p=0·046), associated with a stabilisation of lung function.
The treatment was well-tolerated with no significant difference in treatment-attributable adverse events between groups.
These results demonstrate the potential to halt declining lung function in young CF sufferers and further clinical trials are planned to assess the formulation for transfer to clinical care.