MGX-001 gene-editing therapy shows promise in preclinical study
Good safety, durability seen with hemophilia A treatment candidate in animals
MGX-001, a gene-editing therapy being developed by Metagenomi for hemophilia A, has shown promising safety and durability in an ongoing preclinical study in three nonhuman primates, the company has announced.
Results showed that after one year, two animals had normal (82%) or nearly normal activity levels (41%) of factor VIII (FVIII), the clotting protein that’s missing or is faulty in hemophilia A. The third animal had FVIII activity levels in the mild hemophilia range (9%).
Leveraging on this data, Metagenomi remains on track to file an investigational new drug application — a formal request to the U.S. Food and Drug Administration asking for permission to begin clinical testing in humans — in 2026, according to a company press release.
“We are thrilled to achieve this preclinical milestone supporting our recent decision to declare MGX-001 as our development candidate for hemophilia A,” said Brian C. Thomas, PhD, CEO and founder of Metagenomi. “Our goal for MGX-001 is to provide a one-time, curative treatment for adults and children with hemophilia A.”
Metagenomi tested gene-editing therapy in 3 nonhuman primates
Hemophilia A is caused by mutations in the F8 gene, which provides instructions for making FVIII, a protein needed for the blood to clot. As a result of low levels or activity of FVIII, people with this hemophilia type may experience excessive and prolonged bleeding episodes.
MGX-001 works to integrate a functional version of the F8 gene at a particular site in the DNA sequence of the gene encoding albumin, the most abundant protein found in plasma, the liquid portion of blood. That protein serves as a carrier for many substances in the body.
It does so by packing the gene aboard a harmless adeno-associated virus (AAV) targeting the liver, where most clotting factors are produced. In addition to the viral vector transporting the F8 gene, MGX-001 uses lipid nanoparticles, or small particles made up of fatty molecules, containing a guide RNA and a messenger RNA molecule carrying instructions for making a nuclease, an enzyme that can cut DNA.
The guide RNA is a small molecule that’s designed to direct the nuclease to a specific part of DNA — in this case, to a specific region within the albumin gene. Once there, the nuclease will cut into the DNA sequence of the gene to enable the insertion of the F8 gene.
This gene-editing approach ultimately aims to sustainably increase the activity of FVIII, normalizing blood clotting and preventing bleeds in patients with hemophilia A.
I am encouraged by the preclinical progress in the genome editing space to potentially provide a new path to a one-time, curative treatment option for both adults and children in hemophilia A in the future.
According to Glenn Pierce, MD, PhD, a member of Metagenomi’s scientific advisory board who was himself born with hemophilia A, this treatment strategy could be a game-changer.
“The treatment of hemophilia, which has undergone many transformative changes over the past 60 years, is poised for yet another disruptive change: the use of genome editing, with site-specific integration of FVIII, to produce functional cures in patients with hemophilia A,” Pierce said.
The preclinical study involved first treating the three nonhuman primates with a single intravenous, or into-the-vein, dose of the AAV containing the F8 gene. This was followed by a single intravenous dose of the nanoparticles containing the gene-editing machinery about a month later. The animals underwent a liver biopsy after seven days to evaluate the success of gene integration. They are still being monitored to assess the treatment’s safety and its effects on FVIII activity.
Results from the liver biopsy demonstrated that the gene correctly integrated into the intended DNA region at a frequency of 0.7% to 2.9%, consistent with the reported activity of FVIII.
The treatment was generally well tolerated by the animals, with findings showing a moderate temporary increase in the levels of liver enzymes.
“I am encouraged by the preclinical progress in the genome editing space to potentially provide a new path to a one-time, curative treatment option for both adults and children in hemophilia A in the future,” Pierce said.
About the Author
