Crisper is back: Gene editing to treat Hereditary Angioedema

Hereditary angioedema (HAE) is a rare genetic disease that manifests itself in repeated attacks of edema in various tissues and can lead to life-threatening situations. Now a new drug that combines genetic editing by the CRISPR system is starring in new studies with promising results for patients. Learn more about this new drug and the concept of gene therapy that is gaining momentum in the following article by the medical analyst Meir Fons.

Hereditary Angioedema (HAE) is a rare genetic disorder expressed as recurring episodes of subdermal and submucosal edemas in various tissues, including the extremities, face, pharynx, genitalia, and abdomen. Episodes can be highly painful and even life-threatening. The onset of symptoms usually occurs during childhood and episodes occur throughout the patient’s life, with varying frequency (between a few hours and a few days). Edema occurs due to deficient regulation of the contact activation system (CAS), which consists of three proteins and plays a part in coagulation and inflammatory processes. In HAE, uncontrolled production of the peptide bradykinin by the CAS system causes increased blood vessel permeability which, in turn, leads to fluids exiting the blood vessels into the extracellular matrix – hence the diffuse edemas.

Therapy Targeting the Problematic Enzyme

Bradykinin production is directly mediated by Plasma Kallikrein, one of the CAS system’s three proteins. Normally, Plasma Kallikrein activity is regulated by the C1 Esterase protein, which is responsible for breaking it down and terminating its activity. In HAE patients, there is a deficit or an impairment of this protein’s proper function (hence the disease is also known as C1 esterase deficiency), and so Plasma Kallikrein activity goes out of control. It is no surprise, then, that Plasma Kallikrein became a key therapeutic target for this disease.

In recent years, drugs that inhibit Plasma Kallikrein activity were approved for long-term prophylaxis and offer substantial relief for patients. Additional players have recently joined the race to treat HAE, focusing on reducing Plasma Kallikrein production in the body through RNA interference gene therapies, which interfere with the translation process of the protein’s precursor. Without the precursor, Plasma Kallikrein cannot be produced in high levels.

Innovative Treatment for Patients with HAE

Gene therapy is a medical treatment method intended to create a therapeutic effect by manipulating gene expression or by altering the biological characteristics of living cells. Over 2,900 clinical trials that took place until 2018 led to several regulatory approvals for gene therapies, including Strimvelis for treatment of immunodeficiency, Gendicine for treatment of lung cancer, and Zolgensma for treatment of a muscle weakness disease called SMA. These therapies often use harmless viruses as carrier vectors for introducing corrected genes.

A recently published article describes a small, stage I-II clinical study on gene therapy of HAE using the innovative NTLA-2002 in-vivo gene editing therapy utilizing the CRISPR-Cas9 system (for additional information on the CRISPR system, access our article on gene therapies). The new drug is meant to provide a one-time, systemic treatment by permanent reduction of Plasma Kallikrein levels through direct editing of the gene responsible for its production – KLKB1. This gene-editing complex is embedded in fatty nano-particles to ensure efficient transfer into hepatocytes – the liver cells where the KLKB1 gene is present.

A total of 7 patients, who received the drug at various doses, participated in the study. After taking the drug, Plasma Kallikrein concentrations decreased by about 67%-95% on average, and the frequency of HAE episodes decreased by 91%-97% on average over a follow-up period of 16 weeks.

It’s All in the Genes

The potential of gene editing in management of HAE emphasizes an even broader revolution in the field of personally tailored therapies and the use of CRISPR-Cas9 as a therapeutic tool. While the long-term safety and efficacy of such therapies necessitates further study, the preliminary results from the NTLA-2002 therapy are encouraging, and represent a leap towards a future where many diseases can be managed in a more efficient and accurate manner. As research progresses, one can expect that gene editing therapies such as NTLA-2002 will play a crucial part in changing the therapeutic landscape for hereditary angioedema and other genetic diseases.