Jonathon Kitson has cystic fibrosis. Cystic fibrosis is a disease in which the epithelial cells – the lining of the lung, the interface between your body and the air – produce a faulty protein. That protein causes the mucus that lines the lungs, which would otherwise be thin and watery, to thicken, and become sticky.
Until not that long ago – a few decades – most babies born with cystic fibrosis died within months. Nowadays, things have improved. But only to an extent.
“When I left university in 2017,” says Kitson, a 26-year-old researcher, “I started experiencing more and more chest infections. Cystic fibrosis is a degenerative disease that gets worse as you get older; I’d lived a semi-normal life up to then, but then it got miserable very quickly.”
His lungs’ ability to take in air fell dramatically. “I was down to 28 or 29 per cent lung function,” he says. “I remember once struggling to get up the stairs to put something in the washing basket. I was 24 years old.”
He’d have to go into hospital every couple of months, for two weeks at a time, for intravenous courses of antibiotics, and spend two hours a day on treatments to make him cough up the mucus that was blocking his lungs.
And it would all only go so far. “I was dying, in slow motion. It’s quite something: I was only going to live to about 30, 35. It’s quite a severe mental and physical toll.”
Change a letter, change the word
Genetic diseases like cystic fibrosis are caused by mutations in our DNA. When the sperm and egg that start our lives are made, the DNA is copied from our parents, and sometimes there’s a copying error. Perhaps a few letters in the DNA are repeated, or deleted, or simply mistyped.
We have two copies of most of the genes in our cells – the famous shape of DNA, the double helix, is made of two strands, and there are complementary but not identical copies of each gene on each strand, one from each parent. Most of the time, if we have a faulty copy of a gene on one strand, we have a functioning copy on the other, and the machinery in our cells is clever enough to use the functioning copy.
But that’s not always true. Some people are unlucky, and have two misfiring copies of the same gene. (Or the misfiring gene is on a male person’s X chromosome: the Y chromosome which partners it in men is a stunted thing, and so many of the genes on the X have no complementary copy, which is why some hereditary diseases like haemophilia are far more common in men than in women.)
The genes in our DNA code for proteins, which perform different jobs in our bodies. If the code for one protein goes wrong, as in cystic fibrosis, then it can be devastating.
That’s not just true for cystic fibrosis, of course. Duchenne muscular dystrophy is another degenerative disease, caused by a misfiring of the gene that creates the “dystrophin” protein. It causes muscles to grow abnormally, never attaining full strength; people with the condition rarely live beyond their 30s.
Beta thalassaemia is caused by a mutation that affects a protein in the blood, and prevents it from carrying oxygen as effectively. Sickle-cell anaemia, various immune disorders, several types of hereditary blindness, spinal muscular atrophy, Huntington’s disease: they, and many other diseases, are all caused by single mutations, which affect the body’s ability to make a particular protein.
Adam Rutherford, a BBC broadcaster and a geneticist at University College London, compares it to language. “With cystic fibrosis, it’s caused by the deletion of a single letter,” he says. “Imagine a word where, if you remove one letter, it completely reverses the meaning – from FRIEND to FIEND, or something.”
Fixing a billion problems
It is, now, relatively easy to edit genes. CRISPR-Cas9 is a gene editing tool derived from bacterial DNA which acts as a sort of pair of molecular scissors, allowing you to cut specific bits of DNA out from the genome and replace them. It’s used regularly to edit the genes of viruses, bacteria, animals, plants.
But it’s relatively easy when there aren’t very many bits of DNA to edit. Viruses and bacteria just have their tiny genomes, so that’s fine; in animals and plants the editing is done in the embryonic stage, so there are only a handful of cells to work on.
Grown animals and plants have trillions of cells. In order to cure a disease such as cystic fibrosis, you don’t have to fix every single one of them – “The faulty gene is in every cell in the body,” says Rutherford, “but you don’t have to fix it in, say, the foot, because it’s not doing anything in the foot.” The gene that makes the faulty protein is only switched on in some cells: notably, in the case of cystic fibrosis, in the epithelial cells. But there are still billions upon billions of epithelial cells, and you need to stop a large percentage of them from manufacturing the faulty protein.
That’s where gene therapy comes in. Patrick Harrison, a molecular physiologist at University College Cork, has been working on gene therapy for cystic fibrosis for 15 years. “Most gene therapies are based on genetically modified viruses,” he says. The viruses do what viruses are meant to do: get into your cells, and hijack the machinery of those cells. But instead of getting them to make new viruses, gene therapy orders them to fix the malfunctioning gene.
They don’t, at the moment, do this by editing the damaged gene itself. Instead, they attach a working copy of the gene to it, and the cell is clever enough to use the working one and ignore the broken one. There are plans for true gene-editing therapies, which neatly clip out the faulty gene and replace it, but they’re not here yet. “My crude analogy is between Tipp-Ex and a word processor,” says Harrison. “The current versions Tipp-Ex over the faulty gene and write it in, but with a word processor you could just go in and correct the typo and no one would know it was ever there.”
The difficulty is getting the gene therapy to the relevant cells. Much of the early success has been with congenital blindness: “It’s in the eye, a closed system,” says Harrison. “For a skilled surgeon it’s a simple procedure to inject into different parts of the eye, so the [drug] can’t go anywhere you don’t want.” There’s also been promising work in blood disorders, because the bone marrow which makes the blood can be removed, treated and transplanted back in. “It’s a relatively risky procedure,” says Harrison, ”but if the diseases are fatal in early childhood, it’s a risk worth taking, clinically speaking.” And since everything you put in the bloodstream ends up eventually in the liver, researchers have made a virtue out of a necessity and started looking at liver disorders.
You don’t have to fix every single damaged cell: in the case of cystic fibrosis, for example, the drug simply has to fix enough to reduce the production of sticky mucus to a manageable level.
Two gene therapy drugs have been licensed so far. One, Luxturna, which the National Institute for Health and Care Excellence (Nice) licensed for use in the NHS in 2019, treats Leber congenital amaurosis, a form of retinal deficiency. “It seems to work very well,” says Harrison. “There are some great videos of children who’ve got really poor vision – they can’t walk around a room – and three months later can jump over obstacles and pick up small objects.” The fix doesn’t seem to be completely permanent – “it seems to fade a bit after three or four years” – but it can be given a second time, and that seems to work.
The other drug is Zolgensma, which Nice licensed early last year, for a horrible neurodegenerative disease called spinal muscular atrophy, SMA. Until recently, babies born with Type 1 SMA, the most common and most severe form, usually died before their second birthday. But most of the children treated with Zolgensma survived, and were often able to sit unaided by 16 months. “Seven or eight children in Ireland have received it,” says Harrison, “and it’s proving very efficacious.” It’s early days, but he hopes it will remain effective for years or decades.
Another disease that researchers have high hopes for is Huntington’s, a degenerative disorder which causes nerve cells in the brain to break down. It leads to severe cognitive problems and inability to control movement, and is eventually fatal. It’s caused by a single mutation, and therefore could well be amenable to gene therapy, but there are difficulties.
The mutation behind the disease creates a faulty protein called “huntingtin”. The relevant gene is switched on in the brain, and getting large things like viruses through the blood-brain barrier is difficult. Ed Wild, a professor of neurology at University College London, says “There’s no proven way to get a gene therapy into the brain – unless you drill a hole in the skull and inject it into the brain. So that’s what we’re doing.”
The first patient was treated with this method in June 2020. “They have a very long neurosurgical procedure, 10 or 12 hours under MRI guidance,” says Wild. “Holes are drilled in the skull, thin catheters inserted into the brain region called the putamen.” Then the drug is essentially squirted in. “In theory it should spread to other brain regions like the cortex, and enable them to become a factory for the gene therapy,” says Wild. Researchers hope it will be a one-shot treatment.
The difficulty is that because Huntington’s takes years to progress, it’s very hard to see if it’s working. And it’s hard to recruit people – “A lot of people don’t want to have holes drilled in their skull, especially not knowing if the approach is going to work” – so it may be a long time until we know if it’s working. “People have to hold their nerve with these trials,” says Wild, “because it could be five years or even 10 before you see clear clinical signals.”
Saving lungs and lives
For Kitson, there’s been a breakthrough, and he didn’t have to wait for gene therapy. In the last few years, drugs which act on the production of the faulty protein have been showing real success. “The first couple of weeks were hard,” he says. “It was getting rid of the bad cells, so I was pushing out mucus like never before. But then it felt strange: I can go for long walks, I can go for a jog. I didn’t ever do that, before. I feel normal, now, or what I imagine normal feels like.”
He has gone from three or four hospital admissions a year to one every two years, and those preventative rather than emergency.
But Trikafta, the drug which works so well for him, only works on cystic fibrosis patients with a certain mutation, and has severe side effects in some of those: in total about 20 per cent can’t use it. And it still requires regular treatment for the rest of the patient’s life.
A gene therapy should, in theory, avoid both those problems, but it’s proving challenging. Some early studies have shown that gene therapy is safe and well-tolerated, but they haven’t yet shown great evidence of effectiveness. “The rationale is that if you fix the DNA in enough cells, then it’s rectified,” says Harrison. “We’re not there yet, but there’s a lot of stuff in the pipeline.”
About 12,000 people suffer from cystic fibrosis in the UK alone. Hopefully, in a few years’ time, more of them will have the feeling Kitson has: “I’ll probably live into my fifties, maybe my sixties, potentially longer given the pace of medical progress,” he says. “You’ve been told you’re going to die at 35 and now you’re not, and you haven’t got a pension, have you? It’s this feeling you can do a lot with your life. It’s a good but strange feeling.”