In his office in Oxford’s John Radcliffe hospital, Prof Robert MacLaren sits upright, his back as straight as a soldier’s, and tells me about the lowest point in his 20-year career. It was the rejection, many years ago, of his grant application for a project investigating how gene therapy might treat conditions causing blindness. “It was completely panned by the reviewers,” he says. “We were told ‘There’s no way it’s ever going to happen — it’s a complete waste of time funding such a ridiculously stupid project’.”
In October last year, MacLaren successfully completed the world’s first gene therapy trial for one such condition, called choroideremia, as part of the largest late-stage trial ever for any genetic disease. It marks an extraordinary breakthrough in the quest of scientists and clinicians to understand why and how our own genes can make us ill, and the apparently miraculous possibility of rewriting our genetic code. But MacLaren is understated about this victory: “It’s really satisfying, when you’re given such a rebuttal, to then prove the reviewers wrong. I’d love to go back to them and say: Look what’s going on now.”
MacLaren might like to introduce them to Matthew Bishop, one of the patients from that trial. He is a gardener and a world authority on snowdrops; a softly-spoken, witty man, living in “darkest Devon, where it rains 70 inches a year, with my partner John and no kids, thank God.” Bishop, now 49, was working as a head gardener when his world suddenly caved in. He was driving slowly when he turned his car into the path of another vehicle. “Because my vision had become tunnelled, I didn’t see the other car coming from the left,” he says. “Thankfully we were going at the right speed, so my rear bumper only clipped their front. John was sat next to me and suddenly had his life flashing before him.”
A trip to the optician revealed that Bishop had very little peripheral vision, and he was diagnosed with retinitis pigmentosa, a group of degenerative genetic disorders that affect the retina at the back of the eye. “I said, ‘What’s that?’ and the optician said, ‘Well, you’ll go blind.’ It was as blunt as that. I don’t cry much, but John found me outside the optician’s, sobbing away, a wreck.”
He left his job, and he and John started to redesign their house, for a time when Bishop would need a live-in carer. “There was this massive void, the scary part, the not knowing. What will I do? How will this change my relationship with my partner, my family, my friends? How will I cope with being dependent?” he says.
About two years later, Bishop was referred to MacLaren, who confirmed the optician’s diagnosis and identified the particular condition affecting Bishop as choroideremia, caused by a mutation in a gene called CHM. Suffering from that particular condition, which affects an estimated one in 50,000, he was eligible to take part in MacLaren’s groundbreaking clinical trial — and that meant hope. “Suddenly there was a possibility of no longer going blind. That’s pretty life-changing,” Bishop says.
Robert MacLaren pinpoints the origin of his fascination with the science of sight to his early experiences growing up in Angmering-on-Sea, a small seaside town in West Sussex, where his father was a photographer and his mother a nursing assistant in a care home for the blind. After his PhD, he served in the British army before training in ophthalmology. He now combines NHS clinical work with academia, researching the causes of blindness as a professor of ophthalmology at the University of Oxford.
What makes gene therapy so revolutionary is that it transforms how we think about medicine, MacLaren explains. “The concept is to treat a disease not with proteins or drugs — things that have a general effect on cells — but by modifying the genetics of the cell itself.” When a patient has a gene mutation — meaning a part of the DNA is missing or not functioning, as with Bishop and his CHM gene — gene therapy offers the possibility of correcting that by delivering healthy DNA-like material to replace what is missing.
Gene therapy is the mutation of medicine we need as we hurtle into a hyper-evolved age, MacLaren says: “The human race has spent the last 200,000 years evolving using Darwinian selection: our strong genes have been sustained, the weak genes have died out. These genetic changes, what we call the genetic drift, are still ongoing.” These changes sometimes are an advantage, as weak genes are lost; sometimes they are disadvantageous, causing devastating diseases, he explains — “I have three children. In each of those kids there will be at least 50 to 70 new mutations that my wife and I do not carry, because that’s how DNA evolves. And if those mutations happen to be in a specific, important gene, there will be a genetic disease, and so on for the next generation.” This has huge implications when it comes to the propagation of new genetic diseases — and for how we think about preventive treatment. “Generations from now are going to have to try to treat human disease before the disease takes place. Gene therapy is a very powerful tool to do that.”
His vision of the future is mind-boggling. “We are going to take over Darwinian evolution ourselves,” he says. “We will be able to correct defective genes in people, not by letting them die but by using medicine.” The majority of diseases we suffer from in the developed world involve genetics, he explains, and we could be talking about the eradication of most of these. It sounds like science fiction; how long until it becomes reality? “Within 100 years. We’re going at a massively fast rate, from the discovery of DNA by Watson and Crick in the 50s to the first approved treatment in 2017.”
One of the most difficult questions scientists have faced is how to deliver the replacement genetic material to the cells that need it. They found an ingenious solution: a virus. “A virus is a biological system that has evolved over billions of years to be very efficient at getting into cells and delivering its DNA. If we tried to create a similar organism to deliver DNA in the lab, it would take years — a lifetime. But if we can use an organism that does that already, well, it’s just a case of harnessing the power of that virus,” MacLaren says. Viruses are, in this sense, the Deliveroo drivers of gene therapy.
It has to be a very special kind of virus: one that will not cause any inflammation nor any other side effects. This particular one that MacLaren uses is called adeno-associated virus, or AAV, just 20 nanometres across; MacLaren describes it as “a little stealth virus that has evolved to be completely silent and not do anything”.
Scientists strip the virus of its own DNA, replacing it with the therapeutic gene that is missing from the patient’s DNA — in Bishop’s case, the missing CHM gene. This is then injected into the cells behind the retina, where it behaves like a Trojan horse, releasing the gene hidden inside. The cells adopt this DNA-like material as their own, and “that DNA is expressed, as far as we know, pretty much for the lifetime of the cell,” MacLaren says.
To deliver the virus-turned-Trojan horse to Bishop’s retina cells, MacLaren had to detach the retina from the back of his eye. He shows me a magnified film of an eye during this operation: I see the tip of the syringe, the blob of liquid emerging to sit in a microscopic bubble underneath the retina, the syringe withdrawing, the retina replaced.
Bishop describes it vividly. “After the operation I can remember waking up, and it felt like someone had stuffed all my eyelashes inside my eyeball. It watered like hell, and it was really red.” Only one eye of each of the 14 patients in the trial was operated on: one reason MacLaren chose to focus on the condition of choroideremia is that it is a symmetrical disease, meaning he could measure the efficacy of the treatment by comparing the treated eye with the one that was not treated. The untreated eye deteriorated in three-quarters of patients; but every single one of those who received the treatment successfully, either maintained or improved their vision for up to five years after the operation.
In December 2017, the US Food and Drug Administration approved a form of the treatment for a different kind of inherited blindness . “It’s gone from being purely theoretical to a real, approved treatment with a label on the box,” MacLaren says. Bishop now describes himself as partially sighted; he has no peripheral vision, and will never get back what he has lost. If someone offers him a handshake while he is looking them in the eye, he has no idea, “and they think I’m a rude [expletive] for not shaking their hand,” he says. “It’s a bit bizarre, but it could be a lot worse. Just the simple knowledge that they can prevent any further deterioration has removed the spectre of future blindness. It’s amazing,” he says. “I feel incredibly lucky to happen to have the gene mutation for which they can actually do something.”
There is something particularly poignant about considering yourself lucky to have the right genetic disease. MacLaren uses the same word to describe the timing of his research programme, since so many previous discoveries were necessary to make his treatment possible: the development of the human genome project’s database over the last decade (which aims to sequence and map every human gene), the evolution of virology (the study of viruses); plus the advances in retinal surgery over the last 30 years.
Lucky is a word that also comes up when I speak to Rob and Alison Harding. They live in South Carolina in America, with their son Cameron, five, and daughter Emerson, three; Rob’s son from a previous relationship, Ryan, is 17.
Cameron tells me over Skype that his favourite thing to do is play at the water park with his sister, and his favourite book is about space. It is hard to make out exactly what Cameron is saying, because he has spinal muscular atrophy (SMA), a genetic disorder that causes progressive muscle wasting, with no treatment — at least, not until recently. There is a spectrum of severity of SMA, and Cameron has the most severe form: type 1. Without breathing support, babies born with SMA type 1 are not expected to survive beyond age two. Before speaking to him, I had watched a video on his Facebook page of Cameron dancing and spinning in his wheelchair on holiday in Disneyland, delighting the families watching him. He is a bright and charming child; after a short chat, I thank him for speaking to me and he says, “You’re welcome, have a good day.”
Cameron’s health is very fragile. He uses a manual wheelchair and has a machine to help him breathe at night, as well as one to help him cough and another to help clear secretions because he has a very weak swallow; he is fed through a tube in his stomach. But his spirit, Rob says, is robust. “I love his work ethic. He won’t just sit there and whine for someone to help him. He will find a way, he will figure out how to get what he wants. If he has to scoot on his butt, roll across the floor, grab something with his toes, he buckles down and does what he has to do. That’s my favourite thing about him, because that’s the part you can’t teach.” When I ask him to describe everyday life in their home, Rob says, “Imagine three fire drills going on at the same time, inside a house full of clowns.”
When Cameron was about four weeks old, Alison felt a niggling worry that he didn’t move his arms. She called the doctor and was told to bring Cameron in immediately. They were sent straight to hospital, where a couple of days later, they were told, “We think he has spinal muscular atrophy. There are no treatments, the clinical trials out there today don’t work, go home and just love your child.”
“It was pretty much the worst possible thing you could hear,” Rob says. “Here is this beautiful boy, we’re holding him, he’s alive, he’s in our arms, and they’re telling us he’s going to die, and there’s absolutely nothing that they can do.” Broken by grief, the family of three did as they were told, at first. But Rob could not sit still, he says: “We were sitting at home, mourning him, and I just had to do something. It was the middle of the night, and I got up and started researching, and I came across a clinical trial, led by Dr Finkel.”
Richard Finkel is a gently-spoken paediatric neurologist at Nemours children’s hospital in Orlando, Florida. He has spent the last 40 years working with children who have diseases affecting their nerves and muscles, and over that time, he has seen a breakthrough in the treatment of children with SMA. He tells me over Skype, “SMA is among the most common fatal genetic diseases of infancy and childhood, and it’s a condition that most people have never heard of.” It affects one in every 11,000 children born: they are “typically born totally normal and healthy, they go home, and the parents and paediatrician have no inkling that, lurking beneath the surface, is this deadly disease called SMA,” Finkel says.
A genetic flaw in the SMN1 gene causes certain motoneurons to deteriorate prematurely; these are cells that live in the spinal cord and the brain stem that tell the muscles to contract and relax. When the muscles stop receiving those nerve signals, they atrophy, and the child becomes progressively weaker. “It is a very cruel and hard disease to watch evolve,” Finkel says, “because these babies go from weakness to full paralysis over the course of months or years.”
Until recently, there has been no good news at all for children with SMA and their families. In the early 1980s, fewer than 30 per cent of type 1 babies like Cameron would make it to their second birthday. In the last 20 years, advances in supportive care meant 80 per cent of these babies could survive until two years old and even beyond, but their function continued to decline. There were no breakthroughs.
The first of those came in 1995, when the French geneticist Judith Melki and her colleagues found the genetic cause of SMA, discovering the SMN1 gene, and what Finkel calls the “back-up copy” — the SMN2 gene — both of which produce the protein that is deficient in babies with SMA. Although SMA does not exist naturally in any other species besides humans, researchers could now give animals the disease artificially, and they studied how it developed in mice, pigs, fruit flies and zebra fish. “None of these totally replicates the human condition, but they each give us a clue as to what the disease does to the body, particularly to these motoneurons,” Finkel says. And that meant they could start developing treatments.
The first drug to be developed, known as Spinraza, is what Finkel calls “gene modulation therapy” — instead of targeting the faulty SM1 gene, it targets the SMN2 “back-up” gene, which naturally produces only about 10 per cent of that crucial protein, attaching a strand of DNA-like material to give it a boost and make up for the deficiency. When given to mice with artificially-induced SMA, researchers found that they grew stronger, and instead of dying at 15 days of age were living to over 100 days. But would it have the same impact on humans? It would take a clinical trial to find out — one in which children would receive repeat injections into their spinal fluid via lumbar puncture.
At the time Cameron received his first injection of this drug from Finkel, two weeks after his diagnosis, he had become totally paralysed. The treatment was a huge risk for the Hardings; they did not want to prolong their son’s suffering if there was no hope for a meaningful improvement; and, as it was so new, there were few other parents they could speak to. Ultimately, Rob says, “It also came down to helping to give meaning to his life if he did die, because he would be helping the next child and the next parents who have to go through this.” Taking that decision was a breakthrough in itself for Cameron and his parents. “We were no longer mourning any more, we were no longer planning a funeral — we were focused on the trial, seeing the effects, and contributing to the research,” Alison says.
Even Finkel was amazed by what happened next: “It’s somewhat remarkable. The improvement in the mouse really did predict how these children responded. That’s not usually the case.” Some children did die of the disease. The overall survival rate, however, was vastly improved, and many of those children learned to roll over, hold their head steady, and in some cases even sit. Cameron is not Finkel’s strongest patient — but he’s not the weakest either. To his parents, his improvements are miraculous.
In babies who are treated pre-symptomatically, where SMA has been identified through genetic testing, Finkel says there is an even more rapid and robust response to the drug; many of these babies seem to develop normally, walking and speaking as other babies do, never needing breathing support. In December 2016, Spinraza was approved by the FDA in the US, followed by the EMA in Europe, and it has now been approved in the UK for children with the most severe form of SMA. But in August, Nice decided not to recommend it for use in the NHS, for, among other reasons, cost: the injections for the first year alone cost $750,000 (GBP585,000). There is no treatment for SMA available in the UK.
This is why Aliya Anjarwalla, when I visit her at her house in London, has started packing up her family’s belongings. The first thing she asks me, very politely, is if I would mind washing my hands. It is not just me, she says: every time anyone walks through that door, including her husband Khalil and their two-year-old son Danny, they must wash their hands. Ayden, their chatty, bright, sociable four-year-old, has SMA type 2 — the less severe but nevertheless life-limiting form of the disease — and is at constant risk of catching a bug. That he stays well now is vital, Aliya says, because she and her family are on the brink of a breakthrough of their own.
They have waited long enough. When they were living in Kenya, just before the end of Ayden’s one-year health checkup, she mentioned that her son did not seem able to stand as he could before; whenever he tried to pull himself up holding on to the coffee table, his legs would buckle. After tests for rickets came back negative, the doctor told her: “I don’t know what this is, but you need to do further tests. If you have access to the UK, you should go now.” She was terrified.
The next day, the Anjarwallas hosted Ayden’s first birthday party, welcoming 50 guests into their home. “We felt quite shellshocked. We kept a face on for the party, but we left the next day, flying to London to stay with my parents. That week, Ayden was diagnosed with SMA type 2, on March 26, 2015.” Like the Hardings, they were told there was no treatment.
Over the following six months Ayden stopped being able to pull himself across the floor with his arms. He stopped being able to roll. He stopped being able to lift his arms.
While Aliya was buried by a kind of grief, her husband buried himself in Google. He found out about the Spinraza clinical trial in the US, and the couple told Ayden’s doctor they would move anywhere if it meant that their son could get treatment. They were told they could not participate in trials in another country. They later found out that others had done so. They have not forgiven themselves for not pushing harder. “Since then we’ve almost obsessively been researching clinical trials, and trying to fight our way on to them,” Aliya says. Disappointment followed disappointment, until August 2017, when they managed to meet Finkel.
Aliya speaks of him, as the Hardings do, in a voice reverberating with gratitude. “It was really nice of him to meet us. He spent a lot of time speaking directly to Ayden, explaining what he was doing while he was looking at his joints, immediately putting him at ease.” And he told them about a new gene therapy clinical trial he was leading for children with SMA type 2, like Ayden. This form of gene therapy, produced by the pharmaceutical company AveXis, works like MacLaren’s treatment, using the same viral vector to deliver replacement DNA to the faulty SMN1 gene, by injection into the spinal canal.
The Anjarwallas spent the next year emailing and chasing, arranging meetings and tests for Ayden, and the day we meet, Aliya tells me, “We’re 95 per cent there.” A week or so later, they will fly to Orlando for one last blood test, to check that Ayden has not caught any bugs. If he gets on to the trial, they will stay out there for at least a year; if he does not, they will be back a week later, back to square one. Although they are sad to leave their family and friends in London, they feel they have no choice.
In many ways, Ayden is a typical child. “He’s really into planes, rockets, any kind of vehicle — and he loves construction sites,” Aliya says. But he needs a powered wheelchair, help with cutting up his food and a machine to clear his chest every day. He is also completely adorable — I ask what cartoon he is watching and he shouts, “It’s called Robin Hood!” at the top of his voice. When I ask what he likes drawing, he tells me, “I like to draw pictures.” He plays with my Dictaphone, charming me with a big wide grin.
Since John Bishop had his operation in November 2016, he has regularly returned to Oxford to have his vision measured by MacLaren. The treated eye has remained stable: so far, it is working. Bishop says he was told at the beginning of the trial that he could withdraw any time he wanted. “I thought, ‘Well, why the hell would I do that? This is about helping other people as well — some other poor sod with my condition. If you can do anything that means someone somewhere down the line doesn’t have to go blind, you’re going to do it, aren’t you?’”
Meanwhile, Cameron has grown stronger, as the weeks, months and years of regular injections have passed. His parents watched in astonished delight as he began hitting new milestones, moving his hands, then his arms, then rolling across the floor, even walking, with assistance. Rob says, “At first, my hope was that he could one day twitch a finger to be able to communicate in binary fashion. Now he’s zipping around in a manual wheelchair — he’s blown us away.” “We feel very, very lucky,” Alison adds.
When Ayden and I wave goodbye, I do not know whether he will make it on to the trial — nor, if he does, what difference it will make. “Dr Finkel and others have tried to manage our expectations, saying it might not have a dramatic effect on him, and we know that. We’re under no illusion that it’s going to be some sort of miracle cure,” his mother says. “A lot of damage has already been done. But honestly, even if this treatment just stops the disease in its tracks, that’s huge for us.” Without treatment, she says, “I don’t know what state Ayden will be in in 20 years. I don’t want him to lose the ability to eat, breathe, move his hands, his head. If this treatment stops that, it will change his life, his future — it will change all our futures. There’s a lot riding on this.”
–Guardian News & Media Ltd