Airway Gene Transfer – Enhancing Lentiviral Vector Host/Virus Interactions

The common, monogenic lung disease Cystic Fibrosis (CF) is caused by mutations in the CFTR chloride channel. As founder members of the UK CF Gene Therapy Consortium, we are at the leading edge of developing gene therapy approaches to treat this serious life-shortening disease. Our most clinically advanced vector system is a plasmid/liposome formulation that has recently shown a ~4% improvement in lung function after monthly administration in a Phase IIb clinical trial [Alton 2015]. Our most technically advanced vector system is a novel lentiviral vector that has been specifically pseudotyped to ensure efficient airway gene transfer [Griesenbach, 2012]. This rSIV.F/HN vector is currently entering late-stage efficacy and safety testing prior to first-in-man clinical studies.

We are concerned, that uptake of such revolutionary genetic therapies will be restricted by the high costs of lentiviral vector manufacturing. We have recently identified nine host proteins in lentiviral vector producer cells that dramatically restrict virus productivity (GB patent application 1606717.5, priority date 18th April 2016). We expect an understanding of the interaction of virus elements with these host factors to reveal knowledge applicable to both lentivirus manufacturing and SIV/HIV biology. In this project we will use high-throughput screening approaches to identify additional host factors and CRISPR/Cas9 genome editing tools along with other advanced cell line construction approaches to rationally engineer vector producer cells, boosting virus productivity and reducing manufacturing costs.