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A Phase 2b clinical trial of non-viral gene therapy in Cystic Fibrosis patients: randomized, double-blind, placebo-controlled repeated aerosol delivery to the lungs.

Gill DR

The European Society of Gene and Cell Therapy Conference, Helsinki, 2015

The UK Cystic Fibrosis Gene Therapy Consortium has undertaken an extensive pre-clinical programme, including repeat-dose toxicology studies in mice and sheep, together with a Phase 1/2a safety study in Cystic Fibrosis (CF) patients to assess aerosol delivery of non-viral plasmid DNA/liposomes to the lungs.

The formulation is composed of GL67A liposomes complexed with plasmid pGM169, which 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).

The Phase 1/2a trial in CF patients identified a safe (5ml) aerosol dose delivered to the lungs via a Trudell AeroEclipse II nebuliser. In a follow-on Phase 2b study, CF patients with an FEV1 % predicted lung function of between 50 and 90% were recruited to measure potential clinical benefit following delivery of 12 aerosol doses at monthly (28 ± 5 day) intervals.

The double-blind, placebo-controlled trial compared the above formulation with 0.9% saline in a 1:1 randomisation. The Per Protocol patient group (pre-defined as receiving 9 or more doses) consisted of 116 patients (52 Placebo and 64 Active). Two small (n=24) patient sub-groups also underwent either additional nasal administration, or bronchoscopic measurements, to evaluate molecular surrogates (2:1 randomisation Active: Placebo).

Data for safety and primary/secondary efficacy outcome measures will be presented.

Supported by the NIHR EME programme and the CF Trust.

 

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Other Abstracts by these authors
Aerosol Delivery of Concentrated pDNA/PEI Formulations to the Murine Lung.
Davies LA et al.
The American Society of Gene Therapy Annual Conference (2006) Repeat Administration of Polyethylenimine (PEI) Aerosols of Plasmid DNA to the Murine Lung is Associated with a Loss of Gene Transfer Efficiency.
Davies LA et al.
The American Society of Gene Therapy Annual Conference (2005) Knockdown of ENaCα, as a treatment for Cystic Fibrosis lung disease
Harding-Smith RE et al.
The American Society of Gene and Cell Therapy Annual Conference (2011) Influence of CpG-dinuceotide motifs on the duration of duration of gene expression from plasmid vectors after in vivo lung delivery.
Gill DR et al.
The North American Cystic Fibrosis Conference (2007) EnaC Knockdown in the Mouse Lung using RNAI.
Hyde SC et al.
The North American Cystic Fibrosis Conference (2007) Development, Production and Evaluation of clinical grade CFTR Expression Plasmid for CF Lung Gene Therapy
Gill DR et al.
The North American Cystic Fibrosis Conference (2010)