When Luke Pembroke was diagnosed with the bleeding disorder hemophilia at 11 months old, doctors offered his mother Debra a glimmer of hope – one day, thanks to gene therapy, there could be a cure for the hereditary condition, which made every bump and fall potentially fatal for her loved one. son.
It was a bold prediction in the early 1990s, when the science of gene therapy—the replacement of defective genes with healthy ones to correct incurable genetic disorders—was still in its infancy.
But fast forward nearly three decades and the prediction is coming true, giving hope to thousands of people living with haemophilia in the UK.
According to charity The Haemophilia Society, at least 16 types of gene therapies for the condition are in development. Some are already in clinical trials and could be available on the NHS in the next two to three years.
Although they differ in approach, the goal of each is the same: to correct defective genes – to turn off defective genes involved in causing the disease, or turn on dormant genes that can correct them.
‘I’m very excited about gene therapy – it’s a real advance,’ said Dr Gavin Ling, a hematologist consultant with a PhD in haemophilia and gene therapy from University College London (UCL).
Luke was just a baby when his mother noticed he was bruised. When she took him to the emergency room after finding a large bruise on his head, she was initially greeted with suspicion by doctors who feared she was mistreating her baby. Last year, Luke, now 28, fulfilled a dream trip to the Amazon jungle in Peru (above) to work on a conservation project — something that would have been impossible before.
“It won’t deliver a complete cure for everyone, but if it works, patients will be able to lead much more normal lives for the first time.”
Hemophilia is a genetic condition that affects more than 8,500 people in the UK. It’s because one of the body’s clotting factors — proteins that help form blood clots in case of injury — are missing from birth.
Those affected lack factor VIII (which causes haemophilia A, the cause of 85 percent of cases) or factor IX (which is responsible for haemophilia B, the other 15 percent of cases).
The gene responsible for making these proteins is located on the X chromosome – when damaged, males have only one copy of this (females have two), hence males are mainly affected, although females who carry the defective gene can develop mild haemophilia. Those affected are constantly threatened by uncontrollable bleeding, not only from cuts and abrasions, but also from significant internal blood loss from falls or bumps into the body.
Contact sports, such as rugby, are out of the question and even painkillers like aspirin and ibuprofen are risky because they can inhibit blood clotting even more. The only therapy to date has been regular injections of man-made versions of the missing clotting factors — in some cases every 48 hours.
Luke was just a baby when his mother noticed he was bruised. When she took him to the emergency room after finding a large bruise on his head, she was initially greeted with suspicion by doctors who feared she was mistreating her baby.
“Unfortunately, this is a common story in the haemophilia community,” said Luke, now 28 and creative director at a research firm in London. “Children with haemophilia have severe bruising and sometimes internal bleeding that no one can explain.”
But within hours, a blood test confirmed Luke had haemophilia, and further tests revealed he had type B — the most severe form.
Luke says, “Mommy tells me she remembers sliding down the wall in tears, not knowing what she was going to do next.”
Debra had to come to terms with helping her young child cope with this life-changing illness. That meant learning how to inject him – up to three times a week – with clotting factor, through a needle inserted into a vein.
It was traumatic for both of them. Luke became so afraid of needles that his mother often had to pin him down to get the factor in him. A family video even shows him crying with fear when his mother tried to pin him a birthday badge when he turned two. Even with these regular injections, Luke’s condition was so severe that he still had regular internal bleeding that left him in “indescribable” pain, he says.
Much of this came from bleeding into his muscles and joints, causing long-term damage to the cartilage in knees, hips and wrists – often after a simple trip.
On one occasion, Luke was in bed in constant pain for several weeks when he experienced “excruciating” bleeding into the psoas muscle, which runs from the lower back to the pelvis. Bleeding into muscles like this causes severe pain, as it can damage sensitive nerves in the area.
At school, he was banned from all sports and was bullied by classmates after his head teacher asked him – in a clumsy attempt to give students a better understanding of his condition – to stand at the front of the school meeting as he described his illness.
Luke says, “After that there was a small group of kids who said, ‘If I hit you, will you die?’ When he was seven, a specialist nurse came to the school to teach him to inject himself. “It was very difficult,” Luke says.
“I’d get really mad if I missed the vein.” By the time he was in his twenties, Luke says he had “probably hundreds” of painful bleeding.
When his advisor offered him the opportunity to participate in a clinical trial for a gene therapy drug in 2020, he seized the opportunity.
The 26-week trial – conducted by University College London, the Royal Free Hospital in London and Freeline Therapeutics, the company behind the groundbreaking treatment – involved a single injection of an experimental drug called FLT180a.
Just one dose is designed to deliver a functioning copy of a faulty gene that prompts the liver to produce the protein clotting factor IX, which aids blood clotting in an injury.
The goal, then, is to reduce — or completely stop — the need for patients to inject themselves.
Results of the trial, published in the New England Journal of Medicine in July, showed that in nine out of 10 patients treated with the drug, the liver soon started producing the missing protein after just one injection.
This led to a decrease in bleeding, which meant that patients no longer needed their regular injections of clotting factor. In gene therapy, scientists use the outer shell of a harmless virus called an adeno-associated virus (or AAV) to deliver the new, modified genetic material into cells through a single infusion.
Before starting treatment in February 2020, Luke was given powerful immunosuppressants to prevent his immune system from attacking the virus before it could deliver the genetic material to his liver.
On February 11, 2020, he received his infusion of FLT180a containing the modified gene. Weeks later, the country was plunged into lockdown. To protect him from Covid and other infections, Luke spent eight months in isolation with “terrible” side effects from the immunosuppressant drug tacrolimus and the steroid prednisolone.
“I had every physical symptom you can think of — weight gain, tremors, nausea, and insomnia, as well as migraines, acne breakouts, and mood swings,” he says. “Being alone made everything worse. There were times when I thought, “What the hell have I done?” Luke’s blood was analyzed for clotting factor levels and liver enzymes three times a week, to check if his body was mounting an immune response to the therapy. To reduce the number of nurses coming in and out, he took vials of his own blood.
After eight months he was born again and now he has blood tests twice a year. He is also enrolled in a 15-year follow-up study, which will monitor patients for problems. So far, the benefits far outweigh the risks.
The clotting factor level in his blood has risen and is expected to remain at healthy levels for more than two years. Although he is not cured, this means that his haemophilia is so mild that he no longer needs injections. “I used to be hyper-aware of changes in my body, always afraid I would suddenly bleed,” he says.
Last year he fulfilled a dream trip to the Amazon jungle in Peru to work on a conservation project – something that would have been impossible before. He says: ‘Gene therapy has completely changed my life. I feel free from my haemophilia.’
The Haemophilia Society points out that gene therapy doesn’t work at all in some, and many patients in studies have experienced serious side effects, such as liver problems.
However, scientists hope the same gene therapy techniques could help people with other serious diseases, including type 2 diabetes, as well as sickle cell disease and thalassemia.
A gene therapy trial is underway at University College London to see if injecting chemically modified DNA could help patients with incurable Huntington’s disease (an inherited condition that causes brain degeneration) by turning off a gene that produces toxic proteins.
“In the future, we may have gene therapy consultants that you see alongside your specialist,” predicts Dr Ling.