Intellia Advancing NTLA-2002 as Gene-Editing Therapy Candidate for HAE

Inês Martins, PhD avatar

by Inês Martins, PhD |

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KNG1 and XPNPEP1, rare gene variants

After showing a sustained reduction in kallikrein levels in animal models, Intellia Therapeutics will be moving forward with the development of its gene-editing candidate NTLA-2002 for the treatment of hereditary angioedema (HAE).

The company is now planning to ask regulatory authorities to advance the candidate into clinical studies in the second half of 2021. Intellia’s two other gene-editing therapy programs for other disorders are also on track to enter clinical testing in the near future.

“I am grateful to our team for remaining steadfast in our commitment to patients and putting us in the position to deliver on our goals despite the challenging circumstances presented by the global COVID-19 pandemic,” John Leonard, MD, Intellia president and CEO, said in a press release.

HAE is a rare disorder in which the inflammatory molecule bradykinin is produced in excess. This molecule causes blood vessels to dilate and fluid to accumulate in soft tissues, triggering the sudden and recurrent bouts of swelling that characterize the disease.

The most common cause of HAE is a genetic defect in the SERPING1 gene, which results in low levels or an abnormal C1 esterase inhibitor (C1-INH) protein. But some HAE patients develop the disease due to mutations in other genes.

This means that gene therapies designed to counter mutations in the SERPING1 gene would not be effective in all patients. To address this, Intellia has been working to develop a gene-editing candidate that lowers the bradykinin precursor protein, plasma kallikrein.

NTLA-2002 makes use of CRISPR-Cas9 gene-editing technology to cut off the kallikrein B1 (KLKB1) gene from the DNA. This gene provides the instructions for making the prekallikrein protein in the liver, which is then converted to plasma kallikrein in the blood.

Similar to the company’s other candidates, NTLA-2002 is based on a lipid nanoparticle platform designed to eliminate target genes specifically in the liver, where prekallikrein is normally produced.

The one-time treatment could be used for virtually all forms of HAE and is expected to be safe, as people born with prekallikrein deficiency due to mutations in the KLKB1 gene generally do not show any particular evidence of health problems.

Preclinical studies in non-human primates have demonstrated that Intellia’s gene-editing approach lowers kallikrein activity by more than 90%. The benefits were reproducible and long-lasting, with the most recent reports showing a sustained reduction in plasma kallikrein levels and activity that lasted at least six months after a single dose of NTLA-2002.

“At Intellia, our mission is to develop curative, CRISPR/Cas9-based treatments for severe diseases,” Leonard said. “We continue to advance our full-spectrum pipeline, including … the nomination of NTLA-2002 as our development candidate for the treatment of HAE.”