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, according to the lead researcher.
The patients from New Zealand, the Netherlands and the UK 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 the University of Auckland, Amsterdam University Medical Center and Cambridge University Hospitals have successfully treated more than ten patients with the CRISPR/Cas9 therapy, with interim results just published in a leading journal.
“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.”
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.
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 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.
Dr Padmalal Gurugama, consultant in clinical immunology and allergy at Cambridge University Hospitals, UK 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.”
The therapy affects only the patient and is not passed onto their children, who still have an even chance of inheriting the disorder.
‘A medical magic wand’
One New Zealand patient, Judy Knox, says, “Having had the CRISPR/Cas9 therapy has been like a medical magic wand, it’s changed my life.”
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.
'Once diagnosed Judy, who is a nurse, carefully managed her androgen medication and was prepared to increase it (within prescribed dose) to deal with any flare-ups.
In recent years supply of this medication was not always reliable which became a very real concern for her. Judy knew that there were emergency medications available in New Zealand that, although funded, are still extremely expensive.
When the opportunity to participate in the study came up, she wasted no time volunteering and was one of the first people in the world to receive the CRISPR/Cas9 therapy in 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.”
Another factor was her concern about the continuing availability of the drugs she needed.
Now she has weaned herself off her medicines and feels she has a ‘whole new life’.
To anyone contemplating the therapy, she would say, “Go for it, because it really works.”

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