A groundbreaking gene therapy has been hailed as a “medical magic wand” after the treatment changed the lives of patients with an inherited disorder that causes painful and potentially fatal swelling.
Patients who participated in the first human trial of the therapy experienced a dramatic improvement in their symptoms, and many were able to come off long-term medication and return to normal life.
Dr Hilary Longhurst, the principal investigator at Te Toka Tumai, Auckland City Hospital, said the single-dose therapy appeared to provide a permanent cure for her patients’ “very disabling symptoms”.
Hereditary angioedema, or HAE, is a rare disease that affects about one in 50,000 people. It is caused by a genetic mutation that leaves patients with leaky blood vessels. It causes intermittent bouts of swelling that typically affect the lips, mouth, throat, intestines, hands and feet.
Attacks occur as often as twice a week and last from hours to days. People can become bedridden if the swelling affects the bowel, and its disfiguring effect on the face can prevent people from leaving the house. The most severe flare-ups affect the throat and can lead to suffocation and death.
Cleveland, a 54-year-old from Suffolk who took part in the trial, has been seizure-free since having the therapy 18 months ago. “I had a radical improvement in my physical and mental well-being,” he said. “The randomness, unpredictability and potential severity of the attacks made it almost impossible to try to live my life. I spent my life wondering if my next attack would be serious.
“The swellings are painful and disfiguring. I was ashamed to go out in case of an attack. I was admitted to hospital with swelling on my neck and throat which affected my ability to breathe.”
Judy Knox, a New Zealand nurse who also took part in the trial, said the therapy was “like a medical magic wand”. Before her diagnosis, she developed abdominal swelling with vomiting and severe pain that lasted for days. Dental work caused dangerous swelling in her mouth, which threatened to suffocate her. “It changed my life,” she said.
Knox previously managed the condition with androgen medication, but supplies were not always reliable. She is now off the medication and feels she has a “whole new life”.
HAE is caused by a mutation in the C1 inhibitor gene. When the gene stops working, people produce a protein called kallikrein. This drives the build-up of another protein, bradykinin, which is responsible for the leaky blood vessels and swelling.
Ten patients took part in the small phase one trial in the UK, New Zealand and the Netherlands. Each received an infusion of “nanolipids” engineered using Crispr, a Nobel prize winning no editing tool, to enter liver cells and knock out the kallikrein gene. The therapy stops the body from producing bradykinin, with dramatic effects for the patients.
“It changes patients’ lives,” said Dr Padmalal Gurugama, a consultant in clinical immunology and allergy at Cambridge University Hospital. “My patient had seizures every three weeks and that man had no seizures for the past 18 months. He does not take any medication. It’s incredible.”
The results of the first patients are published in the New England Journal of Medicine, and larger trials are underway. Doctors have treated another 25 patients in a phase two trial and hope to recruit for a final phase three trial next year.
Despite the dramatic results, the therapy is not expected to be available anytime soon. Short of proving itself in the remaining trials, such one-shot gene therapies are down the most expensive treatments in the worldand far from a shoo-in for the NHS.
Prof Paul Morgan, an immunologist at Cardiff University, called the results remarkable. “They demonstrate the potential to permanently cure HAE with a single treatment. Obviously, larger clinical trials, including the different types of HAE in different populations, are now needed,” he said.
Recent reviews have priced one-shot gene therapies at between $1 million (£790,000) and $2 million, meaning the treatments may only be affordable in rich countries, Morgan added. “Nevertheless, this study offers the real prospect of a cure for some HAE sufferers.”
Dr Michael Tarzi, a senior lecturer and honorary consultant at Brighton and Sussex Medical School, was equally impressed. “This is an excellent application of new technology, potentially providing a curative treatment to patients with HAE,” he said.
