‘A magic wand’: World-first NZ gene-editing trial may offer cure for debilitating disorder

A new therapy involving revolutionary gene-editing tech CRISPR-Cas9 may have offered a permanent cure for the rare but debilitating genetic disorder, hereditary angioedema. Photo / 123RF

One of the first human gene-editing trials ever held in New Zealand may have offered a permanent cure for a rare but potentially life-threatening illness.

The Auckland researcher who led the world-first trial, targeting hereditary angioedema (HAE), now sees exciting potential for the cutting-edge tech to be turned against a raft of other genetic disorders.

HAE is a debilitating condition caused by problems with a specific protein, leaving sufferers with unpredictable and often frequent swelling attacks.

Globally, it’s estimated that just 50,000 people have the disorder, with only 60 Kiwi patients so far identified.

For Whangarei nurse Judy Knox and others in her family with HAE, androgen drugs had helped keep the symptoms at bay.

For others who didn’t respond well to medication, however, life could be “absolutely miserable” and beset by constant sickness.

As a young woman in the early 1970s, Knox recalled her tongue swelling so much after having wisdom teeth removed that she struggled to breathe.

“[Patients] used to present with severe abdominal pain and vomiting, and sometimes swelling and other things – but the terrifying thing was that we didn’t know what it was.”

Auckland teacher Rose, who preferred not to give her surname, was diagnosed with HAE as a 5-year-old and spent her childhood in and out of hospital.

“I was quite unwell and missed a lot of school, so it slightly shaped my identity,” said Rose, who was able to start taking self-administered treatments at age 20.

“It’s always been in the back of my mind, when am I going to get a swell, and is it going to be life-threatening?

“I’ve had a handful of throat swells before, and they’re very frightening moments, as you just don’t know when they’re going to stop.”

Clinical immunologist Dr Hilary Longhurst, who’s had a long interest in rare disorders like HAE, described the condition as “horrible” - and also invisible.

“People with it can look completely healthy, but they’re carrying this huge burden,” said Longhurst, an honorary associate professor at the University of Auckland.

“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.”

When Longhurst shifted here from the UK, US company Intellia Therapeutics approached her over trialling its HAE-focused gene therapy in New Zealand, on the basis the country was free of Covid-19 at the time.

“I was doubtful about whether Kiwis would want to do this, but I did feel that it would be a big opportunity,” Longhurst said, adding she was comfortable the treatment would be well tolerated in humans.

How the therapy itself worked was much simpler than many other interventions involving gene-editing.

People with HAE typically had a deficiency of the C1 inhibitor protein, which controlled a biochemical pathway linked to inflammation.

Without enough of this, a protein fragment called bradykinin built up in the body, stimulating swelling.

The therapy was delivered via a lipid nanoparticle, or a minuscule ball of fat, containing CRISPR-Cas9 genetic material, and was 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,” Longhurst said.

Clinical immunologist Dr Hilary Longhurst led a world-first, New Zealand-based trial involving a new gene therapy that appears to have delivered a permanent cure for the rare disorder hereditary angioedema. Photo / Supplied

The gene, KLKB1, produced 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,” Longhurst explained.

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

Knox and Rosie were among seven patients who received the therapy at the New Zealand Clinical Research facility in Auckland, with minimal side effects.

After a single treatment, the participants 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,” Longhurst said.

“It looks as if the single-dose treatment will provide a permanent cure for my hereditary angioedema patients’ very disabling symptoms.”

Fourteen months later, all have been able to stop their HAE medicines.

Knox said she no longer needed to have on hand injected medications, each costing more than $1500.

“It’s been tremendous. It’s like a fairy has waved a magic wand.”

Rosie said attacks that used to cause excruciating pain each week had ceased.

“So, it’s gone from weekly to nothing. It’s like a ‘pinch me’ moment ... it’s pretty mind-blowing to be honest.”

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

Having recently presented the early results, Longhurst was now preparing a randomised, double-blinded, placebo-controlled trial.

More widely, she saw “huge potential” for development of similar CRISPR-Cas9 treatments for other genetic disorders.

“I think we’re at the dawn of a new age of treatments where, if we can pinpoint the gene, we might be able to sort out the problem in a single treatment ... it’s really exciting to be a part of.”

Named Science magazine’s Breakthrough of the Year in 2015, CRISPR-Cas9 has been explored in diseases ranging from cystic fibrosis to hemophilia, with promise for more complex illnesses like cancer, heart disease and HIV.

While New Zealand’s strict regulations around genetic modification have made it difficult to carry out gene-editing research in humans, the past few years have seen several medical trials launch here.

Last August, Carvykti – a treatment in which a patient’s cells are taken and modified to create cancer-killing Car-T cells, before being reinserted to become living drugs – became the second-ever GMO to be approved for uncontrolled release here.

In a regulatory review focused on such lab-contained, biomedical applications, the Government was now looking at whether our gene-editing rules should be focused more on risk than the tech involved.