Intellia linked the largest liver enzyme elevations after CRISPR treatment to a single HLA variant
Intellia added analysis of the immune system gene variant HLA to its phase III CRISPR therapy program after severe liver enzyme elevations
On August 6, Intellia reported an analysis of more than 600 samples from trials of nex-z, a one-time CRISPR therapy for ATTR amyloidosis, a disease in which protein deposits accumulate in tissues. The company linked severe liver enzyme elevations to HLA-C*05:01, a variant of an immune system gene, and added testing for this variant to its phase III documents.
In ATTR amyloidosis, the protein transthyretin, or TTR, forms deposits in tissues and damages the heart or nerves. Nex-z delivers the CRISPR-Cas9 gene editing system to the liver, where it switches off the TTR gene. After a single infusion, the liver produces less new protein.
In a report on the first phase of clinical trials published in 2025, 36 participants received nex-z. The mean TTR level fell by 90% by day 28 and by 92% after two years. Nex-z is now being evaluated in two phase III trials, one in amyloidosis affecting the heart and the other in the hereditary form affecting the nerves.
Some participants developed elevated transaminase levels after dosing. Transaminases are enzymes measured in blood tests and used as indicators of liver cell injury. Intellia observed that these episodes occurred between the second and fifth weeks after infusion and proposed that they reflected an adaptive immune response, which is the immune system's response to a specific target. HLA genes encode proteins on the surface of cells that present short protein fragments to the immune system. Different HLA variants can present different fragments.
The company analyzed more than 600 samples and reported that medically severe transaminase elevations, classified as grade 3 or higher, occurred more often in carriers of HLA-C*05:01. The variant was found in approximately 12% of the samples, and all five of the highest observed elevations occurred in carriers. In the earnings call transcript, Intellia CEO John Leonard described the observation as follows:
“Patients with the C0501 variant had significantly more frequent grade 3 or higher transaminase elevations than the overall group. All five of the highest elevations after dosing occurred in carriers of this variant.”
The phase III documents, including protocols, investigator brochures, and informed consent forms, now include HLA typing to determine whether a participant carries this variant. During screening or before proceeding with treatment, the physician and participant will receive the result and can discuss participation.
The decision must be made before the infusion because the TTR gene has already been switched off afterward. Intellia is therefore using the association between HLA-C*05:01 and enzyme elevations identified in the nex-z program to assess risk during screening.