By Deborah Borfitz 

July 15, 2026 | Patients with hereditary angioedema have reason to be optimistic that regulatory approval of a one-time, in vivo CRISPR gene-editing therapy for the sudden and severe swelling attacks associated with the rare genetic condition could come as early as next year, according to vascular medicine specialist Danny Cohn, M.D., Ph.D., head of the hereditary angioedema clinic at Amsterdam University Medical Center and a principal investigator on the HAELO study investigating the experimental treatment. Lonvoguran ziclumeran (lonvo-z), as it is known, has been under development by Intellia Therapeutics for the past six years. 

The treatment is specifically aimed at treating hereditary angioedema with C1 inhibitor deficiency, the most common manifestation of the disease, and disrupts the KLKB1 gene in the liver to shut down production of the kallikrein enzyme to lower excess inflammation-promoting bradykinin to prevent angioedema attacks, he explains. It is the first-ever phase 3 study of an in vivo CRISPR (clustered regularly interspaced short palindromic repeats) therapy, where the DNA sequences are injected directly into the body to edits cells in place versus being removed from the patient, edited, and infused back (i.e., FDA-approved Casgevy for treating sickle cell disease). 

In the latest randomized, placebo-controlled trial, lonvo-z was linked to an 87% reduction in these attacks (The New England Journal of Medicine, DOI: 10.1056/NEJMoa2600931). Efficacy is expected to rise closer to 100%, as it did for the phase 1 and 2 studies, now that the study has been unblinded, and participants know if they received the active treatment, points out Cohn. There is no reliable biomarker proving any symptom patients experience is a disease flare-up, and they have always been instructed to start treatment as early as possible, so some participants may have erroneously scored mild and incidental throat irritation or abdominal symptoms as an angioedema attack.  

Among other noteworthy study results was that 62% of treated patients remained attack-free without any maintenance therapy, compared to 11% in the placebo group. Key secondary outcomes were also strongly positive, with the need for on-demand treatment falling by 89%, moderate-to-severe attacks decreasing by 91%, and quality-of-life scores pointing to distinctly greater improvement. 

The Unmet Need 

The current reality for patients with hereditary angioedema is lifelong treatments, including on-demand rescue drugs to stop active swelling attacks and preventive therapies to reduce the frequency and severity of future attacks, says Cohn, whose clinic serves over 200 patients. The treatment burden associated with their condition is significant, particularly since the attacks are unexpected and unpredictable. 

When patients travel, they may worry about the availability of cooling or storage for drug treatments and navigating the requirements of airport security. Travel delays can also increase stress, potentially triggering an angioedema attack.  

The prospect of a once-and-for-all treatment intended to last for their entire life is welcome news indeed, Cohn says. Patients lined up to participate in the trials, including 17 of his patients across clinical development of the in vivo CRISPR gene therapy. 

The phase 3 trial enrolled 80 patients who were randomized in a 2-to-1 ratio to receive either the active drug or placebo, he says, but after 28 weeks all those in the placebo group crossed over to the intervention arm. “They knew in the end they would receive the treatment.” 

Importantly, no severe or serious adverse events were experienced, Cohn notes. “There were only very mild and transient infusion-related reactions that resolve spontaneously or with a single dose of acetaminophen.” 

Patients receiving the lonvo-z treatment at his hereditary angioedema clinic indicated that it had a “lifechanging effect,” enabling them to engage in activities they had been unable to do previously, he reports. It provided a solution to an unmet need for patients wanting an attack- and prophylactic-free life. 

‘Beginning of a New Era’

CRISPR was serendipitously discovered by Japanese researchers in 1987. The latest in vivo CRISPR therapy milestone comes only six years after Emmanuelle Charpentier and Jennifer Doudna won the Nobel Prize in chemistry for their discovery of CRISPR/Cas9 genetic scissors that could potentially be exploited as an RNA-programmable genome editing tool (Science, DOI: 10.1126/science.1225829). 

“I think this marks the beginning of a new era where we will undoubtedly see much more in vivo CRISPR results in the future,” says Cohn. A massive number of conditions could potentially benefit from the technology because CRISPR machinery can be reprogrammed to target nearly any sequence in the human genome. 

As of two years ago, Cohn says, over 100 different conditions were collectively under investigation using CRISPR gene editing, both in vivo and ex vivo, and the number has likely increased since then. At Amsterdam University Medical Center, one of the clinical trials underway is using the approach in hopes of reducing LDL cholesterol levels in patients with coronary heart disease. 

Cohn and his team have been investigating kallikrein and prekallikrein (its inactive precursor) as potential targets for hereditary angioedema for nearly a decade now. Having previously shown that reducing kallikrein levels in a patient was highly effective in preventing angioedema attacks, they were invited to participate in the first phase 1 trial of lonvo-z where the treatment easily met its primary endpoint of safety, he reports.   

A strong clinical response was also observed and the subsequent phase 2 trial, where patients were randomized to either 25 or 50 milligrams of lonvo-z or placebo, provided further preliminary evidence that the treatment was highly effective, Cohn continues. In that study, 77% of patients were freed of angioedema attacks initially, but that increased to 31 out of 32 patients following study unblinding. “In the end, all patients that had received 50 milligrams either immediately or after a redose in the phase 1 and phase 2 trials have become completely angioedema attack-free.” 

The next step is for Intellia Therapeutics to submit a biologics license application to the U.S. Food and Drug Administration and equivalent documentation to the European Medicines Agency for hoped-for approval of lonvo-z for the one-time treatment of hereditary angioedema attacks. While regulatory acceptance seems likely, another potential hurdle is the as-yet undiscovered reimbursement process for the treatment since current drug options for which billing codes exist are taken monthly for life. 

If lonvo-z is approved by regulators, the potential beneficiaries include the estimated 1 in 50,000 people diagnosed with hereditary angioedema, says Cohn. Patients are unevenly affected by the condition, and diagnostic delays are a decade or longer in many countries. 

Entire families are affected, he adds. Among the patients he enrolled in the phase 3 trial, one of the key drivers of participation was wanting their offspring to have access to a one-time treatment. The other was to contribute to its development for patients and families at large.