Why Use Gene Therapy to Treat CF?
The basic concept of gene therapy involves introducing a gene into target cells to cure, prevent or slow down the progression of a disease.
CF is a good candidate for this technology as it is primarily caused by mutations in a single gene known as CFTR. A normal copy of the CFTR gene could be delivered to patients via a nebuliser, breathing the therapy into the lungs; a simple approach not requiring any invasive techniques or surgery. This approach would directly target the cause of the disease and could correct many aspects of the complex lung pathology we often see in CF.
A single therapy to treat the underlying defect could greatly reduce the high therapeutic burden of daily physiotherapy, and multiple nebuliser treatments with other drugs that treat some of the symptoms of their disease that CF patients currently have to endure.
One benefit of the gene therapy approach is that one therapy might be suitable to treat subjects with any mutation in the CFTR gene, meaning that a single treatment strategy would be relevant to all CF patients.
Soon after the cloning of the CFTR gene, proof-of-principle for the gene therapy approach was established when the primary problem in CF (a failure to move chloride ions across the cell membrane of affected cells) was corrected after delivery of a functional copy of human CFTR gene to cells isolated from CF patients (Drumm, et al., 1990, Rich, et al., 1990), and to the lungs of mice suffering from CF (Alton, et al., 1993, Hyde, et al., 1993).
Studies in humans followed quickly. Gene therapy for CF has been tested in humans using both liposomes and viruses to deliver the CFTR gene. Five of the liposome trials were undertaken by members of the UK CF Gene Therapy Consortium (Caplen et al., 1995, Gill et al., 1997, Porteous et al., 1997, Alton et al., 1999, Hyde et al., 2000). These early liposome studies showed that gene therapy was safe and worked in principle. However, in these early studies, the effects were too small to have any real therapeutic benefit and only lasted for a few days.
As we improved the liposome approach, we eventually developed a formulation that lasted for many months (Hyde et al., 2008) which when tested in CF patients was shown to halt their decline in lung function (Alton et al., 2015).
Our most advanced form of gene therapy uses a novel viral gene transfer vector that appears to work considerably better than the liposome approach.