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Gene-editing offers hope for people with hereditary disorder

A group of patients with a hereditary disorder have had their lives transformed by a single treatment of a breakthrough gene-editing therapy, a study reports.

The patients from the UK, New Zealand and the Netherlands have hereditary angioedema, a genetic disorder characterised by severe, painful and unpredictable swelling attacks. These interfere with daily life and can affect airways and prove fatal.

Now researchers from Cambridge University Hospitals, University of Auckland and Amsterdam University Medical Center have successfully treated more than ten patients with the CRISPR/Cas9 therapy, with interim results just published in a leading journal.

Dr Hilary Longhurst Dr Padmalal Gurugama
Dr Hilary Longhurst
Dr Hilary Longhurst
Dr Padmalal Gurugama
Dr Padmalal Gurugama

It looks as if the single-dose treatment will provide a permanent cure for my hereditary angioedema patients’ very disabling symptoms. Plus, of course, there is huge potential for development of similar CRISPR/Cas9 treatments for other genetic disorders.

Principal investigator Dr Hilary Longhurst, clinical immunologist at Auckland Hospital Te Toku Tumai and honorary associate professor at the University of Auckland

Globally, it is estimated one in 50,000 people have hereditary angioedema, however, because it is rare, it is often not correctly diagnosed.

In the phase one study, there were no serious or lasting side-effects from the single infusion, which took place over two to four hours under clinical supervision from late 2021 and onwards.

The investigational therapy, called NTLA-2002, utilises in vivo CRISPR/Cas9 technology to target the KLKB1 gene, which is responsible for producing plasma prekallikrein.

By editing this gene, the therapy reduces the levels of total plasma kallikrein, effectively preventing angioedema (swelling) attacks.

The trial, just published in the New England Journal of Medicine, demonstrated a dose-dependent reduction in total plasma kallikrein protein with reductions of up to 95 percent achieved.

A mean reduction of 95 percent in angioedema attacks was observed across all patients through to the latest follow-up.

Patients showing symptoms of an HAE attack on face
Patients showing symptoms of an HAE attack on the face (Image 1 copyright of HAE UK)

The patients from the initial study will be followed up for a further 15 years to continue to assess long-term safety and efficacy.

A larger and more robust, double-blinded, placebo-controlled phase two trial has completed enrolment and a pivotal Phase 3 trial is planned to initiate in the second half of 2024.

The studies have been funded by US company Intellia Therapeutics, which chose New Zealand to lead the research as, at that time – 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 says the gene editing therapy has the potential to significantly improve patients’ lives.

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 Padmalal Gurugama, consultant in clinical immunology and allergy at Cambridge University Hospitals

Dr Padmalal Gurugama and Jacqui Galloway talk about the study and results


Dr Danny Cohn, from the Department of Vascular Medicine at the Amsterdam University Medical Center says these promising results are a step forward for this group of patients.

“We’ve never been closer to the ultimate treatment goal of normalising hereditary angioedema patients’ lives and offering total control of the disease,” says Dr Cohn.

The therapy affects only the patient and is not passed onto their children, who still have an even chance of inheriting the disorder.

Allergy and Immunology Team, Addenbrooke's Hospital, Cambridge
The Allergy and Immunology Team at Addenbrooke's Hospital, Cambridge. From left to right: Dr Charles Lever – Allergy and Immunology Registrar; Kayleigh Atkinson – Research practitioner; Jacqui Galloway – Lead Clinical Nurse Specialist Allergy, Immunology and Research; Dr Padmalal Gurugama – Consultant in Allergy and Immunology; Tom Dymond – Lead Research Practitioner; Rose Swain - Research Nurse; Dr Lisa Shen - Allergy and Immunology Registrar; Ben Montanaro – Research Practitioner

The only UK patient enrolled in the study, 54-year old Cleveland from Suffolk, said the treatment has transformed his life.

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.

Cleveland, who has benefited from the new gene editing treatment

"The randomness, unpredictability and potential severity of the attacks has made trying to live my life almost impossible. I was constantly worrying if my next attack would be severe," he said, and added: "The swellings are painful and disfiguring, I was embarrassed to go out in case of an attack. During severe abdominal attacks, I was unable to move because of the pain. I’ve been hospitalised with swellings on my neck and throat that have affected my ability to breathe."

The swellings caused by HAE exacerbated Cleveland's agoraphobia and severely affected his quality of life. He has since had a radical improvement in his physical and mental wellbeing.

He said: "I can now plan ahead. I can go out for walks, do the shopping or exercise and not be concerned I will have an attack.

"I used to live very close to my family because I was nervous about dealing with attacks on my own. I have been able to move out to be independent and start my own life."

The National Institute for Health and Care Research (NIHR) Cambridge Clinical Research Facility supported this study at Cambridge University Hospitals.