Developing a persistent, inflammation-free gene therapy for Cystic Fibrosis lung disease.

Ian A. Pringle, Stephanie G. Sumner-Jones, Mary M. Connolly, Lee A. Davies, Stephen C. Hyde & Deborah R. Gill.

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Early in 2013 NICE approved a new small-molecule therapeutic for Cystic Fibrosis (CF), a genetic disease where the lungs eventually fail due to repeated bacterial infection. Unfortunately, the drug, costing ~$300K per year per patient, only helps 4% of CF sufferers who carry the G551D mutation in the CFTR gene. For the remaining 96% of CF patients, carrying one of the other >1800 known mutations, the only realistic hope is to find a 'universal corrector' such as gene therapy. Non-viral CFTR gene transfer, where cationic liposomes are complexed with plasmid DNA, can partially correct the ion-transport defects associated with CF, although the effects to date have been transient. In order to offer patients realistic clinical benefit, we further developed our non-viral formulation by: 1) generating a novel plasmid entirely free of CG dinucleotides (CpGs detected by TLR-9), to minimise inflammatory responses; 2) constructing novel promoter sequences capable of persistent CFTR expression in the mouse lung; 3) performing large animal toxicology studies in the sheep lung; 4) procuring the manufacture of >80g of clinical grade plasmid; 5) selecting an nebuliser for delivery of droplets to the CF lung; and 6) performing a dose-escalation Phase I/IIa safety study in CF patients. The results showed that a single dose to the nose and lungs of CF patients administered via a nebuliser was safe and could correct the CF ion transport defect for up to 3 months following a single administration. When the new formulation was repeatedly aerosolised to the mouse lung, there was a dose- dependent increase in CFTR expression in the lungs confirming that our new formulation is suitable for repeated aerosol delivery (once a month for 1 year) to CF patients in a Phase IIb clinical trial. This study is the largest CF gene therapy trial ever conducted (~130 UK patients) was initiated in 2012. To date, over 80 CF patients have received at least one dose. No drug-related SAEs have been observed, and the independent data monitoring and ethics committee has approved full patient recruitment. The results of the study are expected in early 2014.

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