Gene therapy for hereditary angioedema

Last updated Feb. 4, 2025, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

What is gene therapy?

A few gene therapies have been developed in recent years to treat hereditary angioedema (HAE), a genetic disorder marked by recurrent episodes of sudden swelling affecting the deeper layers of the skin or the mucus membranes.

These experimental therapies all share the goal of lowering the frequency and severity of swelling episodes by counteracting the condition’s genetic defects. However, the specific mechanisms through which that’s achieved can vary considerably.

The reason for this is that gene therapy is a fairly broad term used to describe any technique that alters the genetic makeup of cells to treat or prevent a specific disease. It can involve delivering a healthy copy of a gene to a person’s cells, or altering or removing a specific region of DNA to address the underlying cause of a given disease.

Gene therapies also can be classified into two groups, referred to as in vivo and ex vivo gene therapies, depending on where the process of genetic modification takes place.

In ex vivo gene therapies, cells are isolated from a patient to be genetically modified in a laboratory, before being returned to the patient via an infusion. Conversely, in in vivo gene therapies, the process of genetic modification occurs inside the body following the administration of the therapy’s components.

Although no gene therapy currently is approved for HAE, regulatory authorities in the U.S. and other countries have approved gene therapies for a range of genetic disorders, including sickle cell disease, hemophilia, and spinal muscular atrophy.

While side effects are always a possibility with any form of treatment, gene therapy benefits have been transformative for many people with genetic disorders.

How does gene therapy work in HAE?

HAE is a type of angioedema in which swelling attacks are driven by the excessive production of a signaling molecule called bradykinin.

In the most common forms of HAE (types 1 and 2), bradykinin’s higher-than-normal levels are a result of mutations in a gene called SERPING1. This gene provides instructions to make C1-inhibitor (C1-INH), a protein that normally helps regulate bradykinin production but is defective or missing in these HAE types.

More rarely, mutations in other genes can also cause bradykinin levels to become too high, leading to what is referred to as HAE type 3.

Because HAE is caused by genetic mutations, the disease may, in theory, be treated with gene therapies that correct the genetic defects, either in vivo or ex vivo.

Two basic strategies have been explored for HAE in vivo gene therapies. One delivers a healthy copy of the SERPING1 gene to cells in the liver — where the C1-INH protein mostly is made — to restore the body’s ability to produce a functional version of C1-INH.

A second strategy uses gene-editing technology to interfere with the production of kallikrein, an enzyme needed to generate bradykinin from its precursor molecules. By reducing kallikrein levels, the approach is expected to lower bradykinin production, thereby preventing swelling attacks.

An ex vivo approach, in which blood stem cells are first collected and genetically modified in the lab to carry one or more functional copies of SERPING1 before being transplanted back to the patient, has also been investigated.

Potential benefits of gene therapy

Because gene therapies counteract the genetic defects that cause HAE, they hold promise as a one-time HAE treatment.

In theory, it’s possible that these therapies can provide lifelong protection from swelling attacks and free patients from current standard treatments that require regular dosing — but more research is needed to confidently support their lifelong effects in people with HAE.

HAE gene therapies

Although no gene therapy for HAE has yet been approved, a few have been evaluated in preclinical studies, and some have been tested in HAE patients in clinical trials.

Currently, the furthest along in its clinical development is a gene-editing therapy developed by Intellia Therapeutics called NTLA-2002. Another experimental gene therapy by BioMarin Pharmaceutical, called BMN 331, also underwent clinical testing in HAE patients, but the company halted its development in 2024 due to a portfolio reprioritization.

NTLA-2002

NTLA-2002 is an in vivo gene therapy that uses a gene-editing technology called CRISPR/Cas9 to inactivate the KLKB1 gene, which codes for a precursor of the kallikrein enzyme. By disrupting that gene’s activity, NTLA-2002 aims to lower the levels and activity of the kallikrein enzyme, thereby reducing bradykinin levels and ultimately preventing swelling attacks.

A Phase 1/2 clinical trial (NCT05120830) is investigating the effects of ascending doses of this therapy, given via a single intravenous (into-the-vein) infusion, in adults with HAE types 1 or 2. In its Phase 1 portion, 10 patients were treated with NTLA-2002 at one of three doses, and results showed the number of monthly swelling attacks decreased by a mean of 95% for most of them over a follow-up period of about six months to a year. A similar reduction in the number of swelling attacks was observed with a follow-up time of nearly two years.

The trial’s Phase 2 part, which is testing two doses of NTLA-2002 against a placebo, is ongoing. Here, 27 patients were given either NTLA-2002 at one of two doses or a placebo, and then followed for about four months. Results showed that eight of the 11 patients given the highest, 50 mg dose of NTLA-2002 were free from swelling attacks over the course of follow-up, while no patient in the placebo group achieved that outcome. Findings also showed that, compared with the placebo, mean swelling attack rates decreased by about 80% over the course of four months in patients treated once with NTLA-2002 at high dose.

A pivotal Phase 3 clinical trial called HAELO (NCT06634420) also is ongoing into the safety and efficacy of NTLA-2002, at its 50 mg dose, against a placebo in up to 60 adults with HAE. Its main goal is to assess the effect of a single treatment on the rate of swelling attacks over about six months. If all goes well, Intellia is planning to use data from HAELO and the Phase 1/2 study as a basis for applications requesting NTLA-2002’s approval.

Next steps

While some therapies have shown promising findings in HAE clinical trials, a lot of research still must be done before they might be brought to the market. For HAE gene therapies in preclinical development, extremely rigorous safety studies are needed before they can start being tested in people.

For those in early clinical trials, confirmatory studies will need to definitively show the therapies are effective and can be given without unreasonable safety risks.

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