In July 2015, the results of an eagerly anticipated clinical trial of gene therapy in cystic fibrosis were published (Alton et al., 2015).
Cystic fibrosis is one of the most common genetic conditions in the world, and has always been at the forefront of gene therapy research. It is an autosomal recessive disorder caused by mutations in the CFTR gene, which encodes a protein that is involved in the movement of ions across the respiratory epithelium. As a result of mutations in the gene, a faulty version of the CFTR protein is made which either does not work properly, or does not get to the respiratory epithelium. As a result, the fluid balance at the lung surface is disrupted; the lung surface becomes dehydrated, and mucus accumulates. This is an ideal environment for pathogens such as the bacteria Pseudomonas aeruginosa, which cause repeated infections in cystic fibrosis patients that progressively lead to lung damage and ultimately death.
In the past 25 years, there have been about 26 trials of gene therapy in cystic fibrosis, using various viral and non-viral vectors to deliver the correct copy of the CFTR gene. The trial in this paper, which is the largest CF gene therapy trial to date, used a lipid GL67A to deliver plasmid DNA to the lung.
140 patients were recruited to the trial, and they were randomised to receive either aerosolised gene therapy product or a placebo. Importantly, gene therapy appeared to be safe in the trial – there was no difference in the number of adverse events that could be attributed to the treatment in either group.
The trial successfully met its primary outcome measure – a measure of lung function called forced expiratory volume in 1 second (FEV1). Over the 12 months of the trial, patients in the placebo group deteriorated slightly, whilst patients who received gene therapy remained stable. At the end of the trial, there was an overall difference of 3.7% between the two groups (p = 0.046).
Whilst this was a positive response, it has to be said that the effect of gene therapy was very modest. However, the ability of gene therapy to stabilise patients with cystic fibrosis is an important step forward for the field, and encourages future research.
The UK Cystic Fibrosis Gene Therapy Consortium, who conducted the trial, are also working on gene therapy for cystic fibrosis using a viral vector. The group have developed a pseudotyped virus based on the lentivirus SIV (simian immunodeficiency virus), which is showing promise in pre-clinical studies and may be a more potent treatment for cystic fibrosis in the future (Griesenbach et al., 2012).
Alton, E.W.F.W., Armstrong, D.K., et al. (2015). Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 3:684-91
Griesenbach, U., Inoue, M., et al. (2012). Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy. Am J Respir Crit Care Med. 186:846-56