A new treatment for cystic fibrosis (CF) could be available by the end of the decade, say leading scientists who have recently conducted a clinical trial involving gene therapy. “For the first time in the world we have seen a significant benefit in giving gene therapy to cystic fibrosis patients,” said Eric Alton of Imperial College London, the study’s lead researcher. This study is a milestone in the search for a cure, as no major developments in treatment using gene therapy have been made since the gene responsible for the disorder was discovered in 1989.
CF is a hereditary condition caused by the mutated cystic fibrosis transmembrane conductance regulator gene, otherwise known as CFTR, which causes mucus to build up in the lungs. Cystic Fibrosis affects 10,338 people in the UK, 28,103 people in the USA and around 70,000 people worldwide, according to the Cystic Fibrosis Trust.
The symptoms of cystic fibrosis include a recurring cough, infections in the chest and lungs, as well as poor or abnormally slow weight gain. There is no known cure for the disease, and the average life expectancy of sufferers is 41. Although this has risen considerably in recent decades, treatments up until now have involved merely regulating symptoms, such as by using medication to expand airways or to treat infection.
Initial hopes that gene therapy could easily treat the disease proved wishful thinking. The aim of gene therapy is to replace a faulty gene with a healthy, working copy; previous attempts involved the use of a virus as a carrier for the gene which encountered problems as the lungs rejected the virus.
“The lungs must be one of the worst possible organs to go for,” said Professor Alton. “They are so extremely well-defended. With bone marrow you can take it out, do the gene transfer in controlled conditions in the laboratory and put it back in the patient. That is the low-hanging fruit. We have gone for the high-hanging fruit but I’m not at all sorry we have”.
This “high-hanging fruit” that Alton mentions refers to the recent study in which patients ingested liposomes, or fat globules, containing a working copy of the CFTR gene via a nebulizer to get around the problems caused by the virus carrier.
The trial was funded by the Cystic Fibrosis Trust, the National Institute for Health Research and the Medical Research Council, costing a total of £3 million ($4.6 million), and was conducted by scientists from the Universities of Edinburgh and Oxford and Imperial College London. 136 patients were randomly assigned the placebo treatment or the gene treatment. Patients were given 40 minutes of either placebo or gene treatment every month for a year, as stated in the report in The Lancet Respiratory Medicine.
All patients in the double-blind randomised controlled trial had a lung function of 50% to 90%, and all were above the age of 12.
Results showed a 3.7% improvement compared with the placebo treatment, but “the effect is modest and it is variable”, said Professor Alton. “It is not ready to go straight into the clinic yet”. The study was relatively small, and was only a phase 2b trial, which involves assessing the safety and effectiveness of the treatment. What is needed now is a phase 3 trial, which compares and contrasts the treatment with existing ones.
The 3.7% difference in lung function between the two groups of patients equated to a 0.4% reduction in lung function in the gene therapy patients compared to a year previously as opposed to a 4% reduction in a year among the placebo group. So, thus far, the gene therapy trial has resulted in a stabilisation of the cystic fibrosis condition, rather than an active improvement.
Despite this, Stuart Elborn of Queen’s University, who played no part in the trial, says that these results are “encouraging”. Professor Alton goes on to mention that they could “lay the groundwork” for further trials.
These further trials would include the pursuit of two different angles. The first is to give a higher dose of liposome, improving the effectiveness of the treatment by increasing the dose, as well as using drugs known as potentiators that make the CFTR gene more active.
Scientists are also thinking of using a hybrid virus engineered specifically for this purpose to insert a working copy of the gene into the patient. A virus known as lentivirus has been developed, but so far lack of funding has meant that a proper clinical trial cannot get fully underway.
“This is an extraordinary time for therapeutic development in cystic fibrosis,” Ed Owen, chief executive of the Cystic Fibrosis Trust said. “The need is urgent to stop so many young lives being cut short because of this cruel condition.”