Cumulative CFTR expression following repeated aerosol delivery of non-viral pGM169/GL67A formulation to mouse lung.

Sumner-Jones SG, Alton EW, Boyd AC, Davies JC, Davies LA, Dayan A, Gill DR, Griesenbach, U, Higgins T, Hyde SC, Innes JA, McLachlan G, Porteous DJ, Pringle IA, Scheule RK


The European Society of Gene and Cell Therapy, Versailles, 2012

A clinical trial of Cystic Fibrosis gene therapy, delivering CpG-free pGM169 plasmid DNA complexed with cationic lipid GL67A to the nose and lungs, demonstrated safety and molecular efficacy in CF patients.

In preparation for evaluation of this formulation in a Multi-dose trial, the pGM169/GL67A formulation was aerosolised to mice at 2-week intervals for 0.5, 2 or 6hr. The lungs and non-target organs were harvested after one, six and 12 doses.

pDNA and plasmid-specific mRNA were quantified. A significant positive correlation was observed between the quantity of pDNA present in the lungs 1 day after delivery of one, six and 12 doses and aerosol duration. pGM169 pDNA levels in non-target organs were orders of magnitude lower than in lung.

Levels of pGM169- derived CFTR mRNA were low in lungs after a single dose in Low- and Medium-dose groups, with increased signal in the High-dose group. After 12 doses, a cumulative treatment effect was noted with high levels of CFTR mRNA observed in all treatment groups. Robust mRNA levels were maintained for >21 weeks.

This supports our clinical strategy to deliver multiple doses to maximise CFTR expression.