Rob was nearly two years old when scientists discovered the CFTR gene, and its role in CF, in 1989. The breakthrough was heralded as a milestone. Some believed a genetic cure was just around the corner.

Ever since scientists began to understand the genes that are linked to diseases, and the mutations that cause them, gene therapy has been a tantalising prospect. If a mutation is the cause, why can’t we just fix it by replacing the broken part?

On the face of it, CF is a perfect candidate for gene therapy. It’s literally a textbook genetic disease – if you were taught about inherited disease at school in the last 25 years, you’ll likely have studied CF as the example of a simple, one-gene, recessive disease that happens to be relatively common in the Western world. Mutations in the CFTR gene lead to faulty versions of an important protein being made, but only people who have two mutated copies, one from each parent, suffer from CF. People who have only one mutated copy are carriers with no symptoms, approximately one in every 22 people in the UK.

Scientists still do not know exactly how CFTR is responsible for causing the symptoms of CF. The leading theory is that, in people with CF, ions and water do not move across the epithelium, the thin layer of tissue that lines all parts of the body. This makes it harder for tiny hair-like structures called cilia to wave around or ‘beat’, which would normally move mucus and the airborne bacteria it traps out of the lungs and airways.

Yet, theoretically, CF is one of the easiest genetic conditions to fix. Healthy copies of the CFTR gene could be delivered to cells in the lung in much the same way that people with CF already inhale treatments through nebulisers. Once they got into the lung cells, the healthy copies of the gene could make functioning CFTR proteins.

“It was very alluring at the beginning to say I have a gene, I have a delivery device, surely I can get it in,” says Eric Alton, professor of gene therapy and respiratory medicine at Imperial College London. People expected that once you’d identified the broken gene and what it did, you could do gene therapy by adding the normal gene. “Neither of those [discoveries] have been forthcoming rapidly,” he reflects.

The 25 years since CFTR’s discovery seems an awfully long time to wait – and still be waiting. The disease has “contributed much more to science than science has contributed to the disease”, Jack Riordan, one of the gene’s discoverers, told the journal Nature in 2009.

Alton says there is only one barrier to gene therapy – delivery. The difficulty is “you’re trying to put a gene into a lung that is extremely well-defended,” he says. “Your lungs have evolved to keep things out, and we’re trying to put something in. I think it’s no more complicated than that.”

Alton began working on CF the year Rob was born. When a CFTR protein works properly, negatively charged chloride ions move through it, while positively charged sodium ions pass through another channel. This movement of negative charges can be detected as electrical current within the body. Working at the Royal Brompton Hospital in London, Alton began developing a tube that could be inserted into the nose or a lung to measure this electricity. His tool is today used around the world to diagnose people who get indeterminate results from the standard diagnostic tests. “The CF gene was identified in 1989, and then there was the possibility that we could use this diagnostic test as a way of measuring whether gene therapy was successful or not.” He’s been trying to develop a genetic therapy for CF ever since.

The “$64 million question”, as Alton puts it, is how much CFTR function do you have to have for you to be healthy? Someone with two normal copies of the gene, and 100 per cent fully functioning CFTR, will have no lung disease. But the same is true for someone who is a carrier of CF – who has only one normal working copy of the gene and thus 50 per cent CFTR function – they’re still perfectly healthy. This suggests that to cure CF, we don’t need to completely fix it, we just need to fix it enough. The crucial question is how much.

To answer this, Alton points to another related disease, congenital bilateral absence of the vas deferens. Men with this condition are missing the tube that carries sperm from the testes to where they become part of semen, and are thus infertile. This missing part relates to the CFTR gene, and many men who have the disease have CFTR mutations, leaving them with just 10 per cent CFTR function. But these men do not have lung disease.

Alton plots an imaginary graph in the air, of CFTR function versus lung health: people with severe CF on the left, healthy people with two normal copies of CFTR on the right. People with really severe CF who have bad lung disease typically have about 1 per cent CFTR function. “The next point on your graph is CF patients with mild mutations – these patients have quite reasonable lung function, and about 5 per cent CFTR function,” says Alton. The vas deferens condition is associated with about 10 per cent CFTR function, and these men have healthy lungs, just like CF carriers and people with two normal copies of the gene, who have 50 per cent and 100 per cent CFTR function, respectively. “So if you draw a graph, you’ll see you’ve got a sharp slope to start with, and when CFTR function reaches 10 per cent, that should be enough to keep your lungs healthy.”

This makes all the difference. The chances of fully compensating for a broken gene or fully fixing all of a person’s misshapen proteins are slim – to mimic naturally occurring levels of 50 or 100 per cent would be a gargantuan task. But boosting CFTR function from 1 to 10 per cent could be all that is needed to protect from lung disease.

Alton and his collaborators have hit upon a way to get through the lung barrier and deliver those healthy genes to the lung’s cells. DNA cannot enter living cells on its own, but it can be packed inside fatty parcels and smuggled inside. The team use liposomes, microscopic bubbles with an outer layer of fatty molecules that mix easily with the make-up of a cell’s surface. Once inside, the CFTR gene finds its way to the cell’s nucleus, where the genetic material is kept, though exactly how it gets there is still unclear.

The important thing is that the therapy seems to work. The team’s early studies in the late 1990s found that gene therapy could boost CFTR’s electrical activity to 25 per cent on average, a level that Alton believes should theoretically be more than enough to protect a person’s lungs.

After testing the potential of gene therapy, Alton’s team needed to explore how large a dose would be safe but effective enough to use on a long-term basis. In 2009, Rob, then in his final year at Oxford University, enrolled alongside 36 other eager people with CF to take a single dose of the gene treatment. Although this experiment was mainly intended to check the safety of the drug, the researchers got tantalising glimpses of its power. “Some people showed fantastic changes. Some people completely corrected their electrical defect – whilst some didn’t show any change,” cautions Alton, keen not to get too carried away.

It has been such a long time coming that many outside the project – not just scientists but also people with CF and their families – are sceptical. Alton has no doubt that gene therapy will work. “It’s only a question of delivering a gene into a nucleus – it’s not rocket science,” he says. “I have complete scientific faith that it will work at some point.” But the practicalities of such a task are more difficult. Not only must the gene be read by the cell’s own machinery to make the right protein, it must do this on a large enough scale to make a difference to the disease. And over time, as lung cells repair and replicate themselves, repeated doses of the therapy need to be just as effective as the first to be able to sustain any benefits in the long term.

The key test now is to see whether the improvements seen by Alton and his team produce real changes in CF symptoms. “We can get quite reasonable changes in electrical measurements… The question is does that mean anything? If we get 25 per cent restoration of CFTR function, does that mean we’re sitting on the therapy we’re looking for, or that we are a million miles away? You won’t know until you do something repeatedly.”

His aim is to develop something that takes off, even a little, and go from there. “We always say to the patients that we have modest aspirations… like I think the Wright brothers had for the first aeroplane that flew. It didn’t fly every day, it only flew 50 yards, but it proved that powered flight can happen.”