Intellia Presents First Data Supporting CRISPR/Cas9 Gene Therapy Candidate for HAE

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Intellia Therapeutics announced the first preclinical results supporting a gene therapy candidate for hereditary angioedema (HAE). In animal models, the product markedly and sustainably lowers kallikrein activity to levels of expected therapeutic benefit, anticipated to lessen angioedema attacks in patients.

The early data comes on the heels of Intellia’s recently announced HAE program and includes the company’s third genome editing product based on CRISPR/Cas9 technology.

Together with updates in other development programs, the results were disclosed at Keystone Symposia’s Engineering the Genome, held Feb. 8-12 in Alberta, Canada. The presentation was titled “In Vivo Liver Delivery of CRISPR/Cas9 Using Lipid Nanoparticles Enables Gene Knockout Across Multiple Targets and Species.”

“The data from our HAE development program reinforce the modularity of Intellia’s non-viral delivery genome editing platform and how it is enabling independent, single-dose therapies for multiple monogenic diseases,” John Leonard, MD, Intellia president and CEO, said in a press release.

“For HAE, we expect to nominate a development candidate in the first half of this year,” Leonard said.

HAE is a rare genetic disorder characterized by sudden, severe swelling in the deeper layers of the skin that can affect various parts of the body and be life-threatening.

Most cases are caused by a genetic defect in the SERPING1 gene, which results in deficient levels of a protein called C1 esterase inhibitor (C1-INH). This, in turn, leads to an uncontrolled release and buildup of bradykinin, a protein that promotes the dilation, or widening, and permeability of blood vessels, allowing more fluid to leak into body tissues. This leakage causes the episodes of swelling in people with HAE.

The company’s gene therapy candidate was designed to prevent or reduce the overproduction of bradykinin to prevent HAE attacks “with a single course of treatment,” the researchers said. But contrary to other gene therapy approaches that target the faulty gene causing the condition, Intellia’s strategy is to tackle another key player involved in bradykinin production.

It involves completely cutting off the kallikrein B1 (KLKB1) gene from the genome — the complete set of DNA, including all of a person’s genes — a process known in biology as a gene knockout.

The KLKB1 gene provides instructions for making prekallikrein protein, which is produced in the liver and circulates in the bloodstream. In the blood, prekallikrein is converted to plasma kallikrein, which is involved in the release of bradykinin. That is why kallikrein plays a critical role in HAE attacks.

Knocking out KLKB1 prevents cells from making kallikrein, which Intellia expects will bring bradykinin levels down enough to prevent blood vessel leakage and angioedema attacks in patients.

Similar to other company’s candidates, the HAE product is based on a non-viral lipid nanoparticle (LNP) platform that was designed to eliminate target genes specifically in the liver, where prekallikrein is normally produced.

This nanoparticle platform delivers a genome editing machinery called CRISPR-Cas9 to cut out the KLKB1 gene in liver cells. This technology contains two main components. One is a small piece of RNA — a DNA “cousin” — with a short “guide” sequence that binds to the target DNA. The other is the Cas9 enzyme that recognizes the specific DNA sequence and cuts it at the targeted location.

Several potential guide RNAs are being evaluated, Intellia says, and a lead candidate is expected for the first half of 2020.

Removing the KLKB1 gene from liver cells “is expected to be safe,” Intellia reports, as people born deficient for prekallikrein have no particular evidence of health problems.

The results presented show that knocking out KLKB1 in non-human primates leads to a 90% reduction in kallikrein activity in the blood — a therapeutically meaningful reduction expected to lessen HAE attacks, according to clinical studies of kallikrein inhibitors.

Such reduction in kallikrein activity lasted for at least five months and was highly consistent across different animal models, the Intellia researchers report.

Regeneron, currently collaborating in the program, may enter an agreement for developing the HAE candidate. In that case, Intellia will remain the lead party, the company said.