Single dose of new gene therapy has transformed lives of patients with potentially fatal hereditary disorder, say Cambridge researchers

A single treatment of a breakthrough gene-editing therapy has changed the lives of a group of patients with a potentially fatal hereditary disorder - with one patient describing the treatment as “like a magic wand”

The condition hereditary angioedema causes severe, painful and unpredictable swelling attacks, which interfere with daily life and can dangerously affect airways.

But now researchers from Cambridge University Hospitals, the University of Auckland and Amsterdam University Medical Center have successfully treated more than 10 patients from the UK, New Zealand and the Netherlands using a CRISPR/Cas9 therapy.

“It looks as if the single-dose treatment will provide a permanent cure for my hereditary angioedema patients’ very disabling symptoms,” says principal investigator Dr Hilary Longhurst, who is both a clinical immunologist at Auckland Hospital Te Toku Tumai and an honorary associate professor at the University of Auckland.

“Plus, of course, there is huge potential for development of similar CRISPR/Cas9 treatments for other genetic disorders.”

The interim results were published last week in the New England Journal of Medicine and give home to thousands of patients around the globe.

It is estimated one in 50,000 people have hereditary angioedema but its rarity means it is often not correctly diagnosed.

The phase one study found no serious or lasting side-effects from the single infusion of NTLA-2002, which was administered over two to four hours under clinical supervision from late 2021 and onwards.

The investigational therapy use in vivo CRISPR/Cas9 technology - a method of gene editing - to target the KLKB1 gene, which produces plasma prekallikrein.

The edited gene reduces the levels of total plasma kallikrein, which proved to effective at preventing angioedema (swelling) attacks.

The researchers found the therapy reduced up to 95 per cent of the protein - and they observed a mean reduction of 95 per cent in angioedema attacks across all patients through to the latest follow-up.

They intend to follow up the patients from the initial study for a further 15 years in order to assess its long-term safety and efficacy.

Meanwhile, a longer, more robust double-blinded, placebo-controlled phase two trial has completed enrolment. A phase 3 trial is due to start in the second half of the year, with all the studies funded by the US company Intellia Therapeutics.

It chose New Zealand to lead the research because at the time, in late 2021, it had relatively fewer Covid-19 cases than other countries.

Dr Padmalal Gurugama, consultant in clinical immunology and allergy at Cambridge University Hospitals, said: “Hereditary angioedema can cause patients severe swellings and intense pain which can be life-threatening as well as restricting normal activities, such as going to work or school.

“Because it is often misdiagnosed, many patients undergo unnecessary treatments and invasive procedures.”

Dr Danny Cohn, from the Department of Vascular Medicine at the Amsterdam University Medical Center, added: “We’ve never been closer to the ultimate treatment goal of normalising hereditary angioedema patients’ lives and offering total control of the disease.”

The gene editing will only impact the patient and not be passed onto their children, meaning they have an even chance of inheriting the disorder.

One UK patient who received the treatment, Cleveland, told of the debilitating nature of the condition, explaining: “The randomness, unpredictability and potential severity of the attacks has made trying to live my life almost impossible. I spent my life constantly wondering if my next attack would be severe.

“The swellings are painful and disfiguring. I was embarrassed to go out in case of an attack. I’ve been hospitalised with swellings on my neck and throat that have affected my ability to breathe.

“Since the treatment, I’ve not had a single attack. I’ve had a radical improvement in my physical and mental wellbeing.

“I am very positive about the future. I am now volunteering where I can meet like-minded people. The freedom has opened up my world and improved my self-confidence.

One New Zealand patient, Judy Knox, suffered abdominal swelling with vomiting and severe pain that could last several days before she was diagnosed.74

Dental surgery would lead to dangerous swelling in her mouth, including her tongue, palette and throat, that was extremely painful and threatened to suffocate her.

Before she was diagnosed, Judy would get abdominal swelling with vomiting and severe pain that could last several days.

Dental surgery could prompt dangerous swelling in her mouth, including her tongue and palette, and her throat that were excruciatingly painful and threatened to suffocate her.

Following diagnosis, Judy, a nurse, managed her androgen medication and was prepared to increase it within the prescribed dosage to deal with any flare-ups.

But the supply of this medication has not proved reliable in recent years, causing her great concern. While there were emergency medications available in New Zealand that were funded, they remained very expensive, so Judy was quick to volunteer for the study, becoming one of the first people in the world to receive the CRISPR/Cas9 therapy at a clinical research centre in New Zealand.

“I put my hand up and said, ‘I'll do it.’ And because it was beneficial to others,” she said. : “Having had the CRISPR/Cas9 therapy has been like a medical magic wand - it’s changed my life.”

She has now weaned herself off her medicines and said it is like a “whole new life”, telling anyone who may in future consider the therapy: “Go for it, because it really works.”