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Gene-editing Treatment Relieves Debilitating Symptoms

Kiwi patients with a painful and debilitating inherited illness say gene-editing therapy has changed their lives.

Kiwi patients with a painful and debilitating inherited illness say gene-editing therapy has changed their lives and completely relieved their symptoms.

The group of seven patients who participated in a clinical trial have hereditary angioedema, meaning they formerly experienced unpredictable, sometimes frequent and potentially lethal attacks of swelling.

They were treated in late 2021 and early 2022 in the New Zealand Clinical Research facility in Auckland, as part of a first-in-human clinical trial of the CRISPR-Cas9 gene-editing 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 Honorary Senior Lecturer Dr Hilary Longhurst. “Plus, of course, there is huge potential for development of similar CRISPR-Cas9 treatments for other genetic disorders.”

People with hereditary angioedema find the attacks of swelling impact on their ability to take up normal opportunities in work and life.

The attacks may occur several times a week or a few times a year.

Over a lifetime, the disorder is associated with significant anxiety and depression.

The patients who participated in the trial are reporting that the therapy has been “life-changing”, says Dr Longhurst.

“Many of the patients have had family members who have died and they are absolutely terrified,” Dr Longhurst says. “They are frightened both of the pain of abdominal attacks, which is comparable to that of heart attacks and childbirth, but also the fact their airways might swell up and they might suffocate.”

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Globally, it is estimated one in 50,000 people have the hereditary angioedema, which means it is likely 100 New Zealanders have the condition. However, because it is rare, it is often not correctly diagnosed. So far only around 60 Kiwi patients have been identified.

Patients have an inherited deficiency of the C1 inhibitor protein, which controls a biochemical pathway linked to inflammation. Without sufficient C1 inhibitor, the body gets a build-up of a protein fragment (peptide) called bradykinin, which stimulates swelling.

The therapy is delivered via a lipid nanoparticle, or miniscule ball of fat, containing the CRISPR-Cas9 genetic material, and is infused through a vein in the patient’s arm over two to four hours.

“This ball of lipid targets the treatment into the liver, and then the CRISPR guides the Cas9 onto exactly the gene that is causing the problem,” Dr Longhurst says.

The gene, KLKB1, produces a protein precursor to bradykinin, called kallikrein.

“The CAS9 acts as a molecular scissor to cut the KLKB1 gene. The body heals the break in the KLKB1 gene, but in doing this it sows additional bits of genetic material so that gene doesn't work anymore.

“The effect of the treatment is to silence the KLKB1 gene and to prevent overproduction of the kallikrein and bradykinin that cause the swelling.

“I always warn the patients that they may feel fluey on the day of the treatment but in fact the symptoms have been minimal,” Dr Longhurst says. “Some people feel a bit tired or have a headache, and one person had a bit of a temperature that lasted a few minutes. It’s been incredibly well tolerated.”

After a single treatment, the patients either had no more attacks of swelling or a dramatic reduction and then cessation of attacks after a few weeks.

“One patient, who had been experiencing frequent severe attacks, took a while to settle down, but most were immediately attack-free,” says Dr Longhurst.

By January 2023, ten months 14 months after the first treatment, almost all the patients have been free of attacks for between two and ten months and all patients have been able to stop their previous angioedema medications. The exception was a minor hand swelling after a sports injury, which technically classified as a potential angioedema.

Dr Longhurst, an Honorary Associate Professor of Medicine at the University of Auckland, presented results from the trial at a November meeting of the American College of Allergy, Asthma and Immunology, with the abstract published in the Annals of Allergy, Asthma & Allergy (November 2022).

The US company, Intellia Therapeutics, chose New Zealand for the first-in-world trial as the country had relatively little Covid-19 at the time, late 2021.

Since the New Zealand trial, family members of participants and patients in the Netherlands and the UK have received the same treatment.

The next stage will be a randomised, double-blinded, placebo-controlled trial.

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