CTX450 gene-editing therapy shows promise in AHP mouse model

CRISPR Therapeutics expects to launch first human trial testing CTX450 in 2025

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by Steve Bryson, PhD |

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Illustration of hand holding a mouse next to some test tubes of red liquid.

CTX450, an investigational gene-editing therapy for acute hepatic porphyria (AHP), was able to normalize disease-associated biomarkers in a mouse model, showing its potential as a one-time intervention for the disease.

CRISPR Therapeutics, the treatment’s developer, plans to launch studies to secure approval for first-in-human clinical trials, which are expected to begin in the second half of 2025.

“The expansion of our in vivo pipeline speaks to the scalability of the platform and the exceptional translation capabilities of our team,” Samarth Kulkarni, PhD, CRISPR’s CEO and chairman of the board, said in a company press release. “We continue to add programs to treat both common and rare diseases, as we look to broaden the number of areas where CRISPR could have transformational impact.”

AHP comprises a group of porphyrias marked by the harmful buildup of porphobilinogen (PBG) and aminolevulinic acid (ALA), two intermediary products created during the production of heme — a molecule that enables oxygen transport in the body.

At high levels, ALA and PBG are harmful to nerve cells and are thought to cause chronic AHP symptoms and acute attacks marked by severe abdominal pain, neurological symptoms, and muscle weakness.

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ALAS1 enzyme is overactive in people with AHP

Contributing to the rise in ALA and PBG levels is an enzyme in the liver called aminolevulinate synthase 1 (ALAS1), which is overactive in people with the disease.

Delivered to the liver using small particles made up of fatty molecules (lipid nanoparticles), CTX450 uses the CRISPR/Cas9 gene-editing tool to edit the gene that provides instructions for making the ALAS1 enzyme. The goal is to lower the production and levels of the enzyme, thus preventing PBG and ALA from building up and causing disease attacks and other symptoms.

In an AHP mouse model, CTX450 successfully edited the ALAS1 gene in about 70% of liver cells and lowered ALAS1 enzyme production by approximately 97%. As a result, levels of PBG and ALA were normalized.

The success of CRISPR’s gene-editing technology has been demonstrated by the recent approval of the gene-editing therapy Casgevy (exagamglogene autotemcel) for people with sickle cell disease and transfusion-dependent beta-thalassemia, a related blood disorder.

The company is also developing liver-targeted CRISPR/Cas9-based treatments for cardiovascular disease, including CTX310 and CTX320, which are currently undergoing clinical testing, and CTX340 for hard-to-treat high blood pressure.

In addition to the liver-targeted pipeline, preclinical studies have supported the editing of genes in the eyes to treat glaucoma, the second leading cause of blindness worldwide.

“Over the past two years, we have made significant progress on the development of our lipid nanoparticle platform for the delivery of CRISPR/Cas9 to the liver and are now in clinical trials with CTX310 and CTX320,” Kulkarni said.