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.