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LOUISVILLE, Ky. -- The future medical promise of CRISPR/Cas9 gene-editing appears to be a present-day reality for a small group of patients with the rare genetic condition known as hereditary angioedema (HAE).

Interim results reported here from a phase I/II study involving 10 HAE patients showed a single infusion of a CRISPR/Cas9-based treatment to be associated with no significant safety concerns and dramatic declines or elimination of swelling episodes over 16 weeks of follow-up.

One patient who averaged 3 swelling attacks per month before treatment with a single 25-mg infusion of the investigational treatment (NTLA-2002) had no attacks in the 16-week post-treatment period, according to Hilary Longhurst, MD, of the University of Auckland in New Zealand, who presented the first-in-human data at the annual American College of Allergy, Asthma & Immunology meeting.

Swelling attacks also declined in three patients receiving single 75-mg infusions of the therapy at 16 weeks post-treatment. In one patient, average monthly attacks declined from 6 to 3.5; in another, from 4 to none; and in the third, from 4 attacks per month to 0.3.

Longhurst noted that while HAE affects only about one in 50,000 people worldwide, it can dramatically impact patients' quality of life, and can even be fatal in cases where swelling restricts breathing.

"Patients are absolutely terrified, not just of laryngeal attacks, which can be fatal, but also of abdominal attacks, which are exquisitely painful," she said. "And there is a huge burden in terms of both psychological and economic damage that comes with a diagnosis of HAE."

In patients who do not receive treatment, swelling attacks typically occur every 7 to 14 days. Prophylactic treatments target kallikrein, which is encoded by the KLKB1 gene. While these therapies significantly reduce the frequency of attacks, they are also expensive, with some drugs approved for attack prevention costing hundreds of thousands of dollars per year.

"We know that when you inhibit kallikrein you get very effective control and prevention of HAE," Longhurst said, adding that silencing the prekallikrein KLKB1 gene has been shown to be associated with complete attack control.

"So we hypothesized that if we used a CRISPR/Cas9 approach to edit out the prekallikrein gene we would get lifelong prevention and control of HAE-related symptoms," she said.

The researchers also hypothesized that editing out the gene would be safe, based on the observation that people with a prekallikrein deficiency syndrome known as Fletcher disease tend to have no deficiency-related symptoms.

The primary objective of the phase I open-label first-in-human trial was to evaluate the safety and tolerability of a single infusion of the investigational prekallikrein-targeting drug NTLA-2002 at three doses; 25 mg (n=3), 50 mg (n=4), and 75 mg (n=3).

Longhurst presented post-infusion, week-16 efficacy data for three patients each in the 25-mg and 75-mg arms of the study.

The median age of the 10 patients included in the trial was 51 years (range 26-73 years), and six were male.

All patients received the full assigned dose of NTLA-2002, and the majority of reported treatment-emergent adverse events (TEAEs) were mild to moderate (grade 1/2). No serious adverse events or grade 3 TEAEs were reported.

Longhurst noted that NTLA-2002 infusions were associated with rapid and sustained declines in plasma kallikrein reductions at all dose levels, with 64% (25 mg group), 81% (50 mg group), and 92% (75 mg group) reductions reported roughly a month after treatment.

In an interview with 番茄社区app, Longhurst said a larger study of NTLA-2002 should be underway early next year.

If future trials continue to show NTLA-2002 to be both safe and effective for the prevention of HAE swelling attacks, the CRISPR/Cas9 therapy could prove to be a cost-effective alternative to currently available prophylactic treatments.

Longhurst said she is excited about the many potential future applications for gene editing in the treatment of rare genetic diseases like HAE and more common diseases.

"Monoclonal antibodies changed people's lives when they became available decades ago, and I think this may be the next medical advance that could do that," she said. "It is amazing to be part of that."

Jay A. Lieberman, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee, also spoke to 番茄社区app about the early NTLA-2002 data.

"Obviously these findings are very preliminary. It is very early, but fascinating," he said. "If this approach works -- and the early data suggest that it does -- this one-time therapy might lead to long-term or even permanent symptom relief. That would be beyond amazing."

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