Eric Alton says there is only one barrier to gene therapy for cystic fibrosis: delivery, “the fact that you’re trying to put a gene into a lung that is extremely well-defended. Your lungs have evolved to keep things out, and we’re trying to put something in.”
In some respects, genetically modified viruses seem ideal. The microorganisms have spent millions of years evolving ways to put their genes into your cells – when you get a cold, a virus has got its genes into your respiratory cells. But just as you beat a common cold by developing immunity to the virus that has infected you, many gene therapy viruses can be administered only once before they stop being effective.
Early attempts to use viruses as gene therapy vectors have also shown that extreme care is needed when using them to alter a patient’s genome. The type of viruses that have been used to give gene therapy to ‘bubble boys’, who have no immune system, brought with them a high incidence of leukaemia.
Faced with these difficulties, Alton, professor of gene therapy and respiratory medicine at Imperial College London, says that the critical choice taken by UK researchers was to develop a liposome vector – made of fatty molecules that mix easily with the make-up of a cell’s surface – for gene therapy instead.
Experiments show that this method of gene delivery works in some, but not all, people. “Viruses are clearly going to be better at getting the gene into the right cell,” says Alton. “But we went for the liposome because we could see that we could administer it to patients repeatedly, without them becoming immune.” This is important because, once a foreign gene has been inserted into a cell, it is not able to function there permanently as it will get switched off.
Alton says that the liposome method is just the UK Cystic Fibrosis Gene Therapy Consortium’s first attempt at an effective, usable genetic drug. “We’re making the assumption that it may not be the final answer.” While the group are forging ahead with the liposomes, they’re also working on a viral therapy that they hope will one day be more effective. Like viral vectors that have been trialled in past, this therapy is based on a virus that can insert itself into the human genome, potentially affecting cancer-related genes. But the group are looking at a specific sub-class of integrating viruses called lentiviruses, which they believe might be safer than those viruses previously used for gene therapy.
“Can I say they’re safe? No, because otherwise we would have taken lentiviruses into the clinic today, why wait?” says Alton. Instead, the consortium are conducting a 30-month toxicology study of the virus to test its safety. If convinced, Alton says the plan is to trial this second-wave genetic therapy in people with CF in 2017.