CRISPR therapy treats rare genetic inflammatory disorder

A single dose of a CRISPR-based gene therapy could cure inflammation in people affected by a rare condition that causes life-threatening swelling attacks, according to a new clinical trial.

Researchers in New Zealand and the Netherlands have developed a gene therapy for the treatment of hereditary angioedema, a genetic condition that causes unpredictable inflammatory attacks that can result in potentially fatal obstruction of the airway.

'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,' said Dr Hilary Longhurst, clinical immunologist at the University of Auckland, New Zealand, and lead author on the study.

Publishing their findings in The New England Journal of Medicine, the researchers studied a group of ten people affected by hereditary angioedema, with one enrolled from the UK and the rest from New Zealand and the Netherlands. Patients were divided into three groups and treated with different single doses of the gene therapy, with all groups showing substantial reduction in the swelling symptoms. There were no serious side effects observed in the patients aside from fatigue.

'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', said the UK trial participant, identified only as 'Cleveland', from Suffolk. Describing living with the condition prior to the clinical trial he said: 'The swellings are painful and disfiguring… 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'.

In hereditary angioedema patients, an increased activity of a plasma protein, called kallikrein, causes fluid leakage from blood vessels, promoting tissue swelling. The gene therapy, called NTLA-2002, uses CRISPR/Cas9 to introduce small deletions and insertions to disrupt kallikrein production and thereby reduce its plasma levels.

NTLA-2002 is administered by directly infusing the treatment into patient's blood, with the genome editing components encased in lipid nanoparticles that cells can take up. This is different from the first (and currently only) CRISPR-based gene therapy approved in the UK (see BioNews 1216), where target bone marrow cells have their genomes edited outside the body before being transplanted back into the patients.

'This is an outstanding application of new technology, which potentially offers a curative treatment to patients with hereditary angioedema,' Dr Michael Tarzi, honorary consultant at Brighton and Sussex Medical School, who was not involved in the study, told the Guardian.

The clinical trial participants will now be monitored for the next 15 years to assess the long-term safety and efficacy of the gene therapy. Phase 2 and 3 trials to evaluate its benefits in larger cohorts will start later this year.