Executives from Epicrispr and Metagenomi (NASDAQ:MGX) outlined next-generation gene regulation and gene-editing approaches at a Chardan discussion focused on platforms beyond conventional CRISPR gene cutting.
Chardan Senior Biotech Analyst Keay Nakae said traditional CRISPR approaches use guide RNA to direct an enzyme to a DNA location, where it creates a double-stranded break. The panel examined alternatives designed to regulate genes without cutting DNA or to support targeted insertion of therapeutic genes.
Epicrispr Highlights Epigenetic Regulation Strategy
Salzman said Epicrispr deactivates the nuclease activity of Cas molecules so that they bind to a target without cutting DNA. The company then attaches proprietary modulators intended to precisely control gene expression. She said this approach could be particularly important in diseases where increasing expression too much could be toxic, such as certain haploinsufficiency disorders.
“Rather than cutting the DNA and really taking that brute force approach,” Salzman said, Epicrispr seeks to control gene regulation with greater precision. She also said the approach may offer safety advantages because unintended epigenetic effects in non-coding DNA may be less consequential than unintended DNA cuts, while noting that the company continues to assess off-target effects.
Epicrispr’s lead candidate, EPI-321, is being developed for facioscapulohumeral muscular dystrophy, or FSHD. Salzman said the disease is associated with expression of DUX4 resulting from a hypomethylated genomic region. EPI-321 is intended to bind upstream of DUX4 and suppress its expression.
She said FSHD was a deliberate initial target because adeno-associated virus, or AAV, is clinically validated for delivery into muscle but has limited payload capacity. Epicrispr’s proprietary Cas molecule is compact enough to fit in an AAV vector alongside its modulator and guide RNA, according to Salzman.
Early FSHD Data Include Muscle and Biomarker Findings
Salzman said the company completed dosing of 12 patients in its study, including six at a starting dose and six at a higher dose. The first six patients had reached their six-month visits, and interim results were presented by a principal investigator at the World Muscle Society meeting.
According to Salzman, all six patients gained lean muscle volume on imaging, despite projections that they would lose lean muscle volume based on the disease’s expected progression. She said quantitative muscle testing also showed strength gains in maneuvers associated with the areas where patients gained lean muscle volume.
The company also reported a reduction in ZBTB17, a direct transcriptional target of DUX4 that Epicrispr refers to as DUCZ. Salzman said the biomarker findings supported target engagement.
Epicrispr compared patient outcomes with “digital twin” projections generated by Springbok Analytics using machine learning models based on prior MRI data. The company also compared results with external natural-history data, including data made available from Fulcrum studies. Salzman said the company used propensity-score matching to identify patients in the historical data set who most closely resembled patients enrolled in its trial.
Epicrispr expects to report 12-month data from 12 patients in 2027, Salzman said.
Metagenomi Details Hemophilia A Gene-Insertion Program
Metagenomi CEO and President Jian Irish discussed MGX-001, the company’s program for hemophilia A. Irish said the company is pursuing a potential one-time treatment designed to insert a factor VIII gene directly into the chromosome, differentiating its approach from BioMarin’s Roctavian, which delivers the factor VIII gene episomally.
MGX-001 uses an AAV-delivered factor VIII DNA template and a separately delivered lipid nanoparticle containing mRNA for Metagenomi’s CRISPR nuclease and a guide RNA. The nuclease makes a targeted cut in the albumin gene, allowing the factor VIII sequence to integrate into that location and use the liver’s machinery for expression, Irish said.
In juvenile non-human primate studies, Irish said factor VIII activity reached peak levels within two weeks after dosing and remained stable through approximately 19 months of follow-up. He said activity correlated with measured integration, supporting the intended mechanism. In a dose-ranging primate study, most animals in target dose cohorts reached the normal factor VIII activity range of 50% to 150%, and no animals exceeded the 150% upper limit.
Irish said Metagenomi intends to initiate a Phase I/II, single-arm, open-label, multicenter study next year, following discussions with the FDA in pre-IND meetings. He said the trial is expected to include U.S. and international hemophilia treatment centers.
Manufacturing and Steroid Considerations
Irish said the company’s use of the endogenous albumin promoter eliminates the need to include promoter elements in its AAV cassette, which he said could help preserve AAV genome integrity during manufacturing. He also said the company observed normal factor VIII activity at an AAV dose of 5e12 vg/kg in preclinical studies, which he described as more than 10 times below the Roctavian dose level.
Metagenomi has completed manufacturing and released batches for clinical supply, Irish said. He added that its proprietary MG29-1 type V nuclease uses a shorter guide RNA, which the company believes may support improved synthetic RNA yield and purity.
On corticosteroid use, Irish said Roctavian’s prolonged steroid treatment has been a concern for clinicians. He said Metagenomi observed only mild, transient liver-enzyme elevations in preclinical studies after one prophylactic steroid treatment before AAV and lipid nanoparticle dosing. The company expects to monitor immune burden and steroid requirements closely in the planned clinical study.
About Metagenomi (NASDAQ:MGX)
Metagenomi, Inc is a biotechnology company focused on developing genetic medicines using gene-editing technologies. The company applies metagenomics, the study of genetic material recovered directly from environmental samples, to identify naturally occurring CRISPR and other genome-editing systems that may offer advantages over established tools.
Metagenomi is developing a pipeline of investigational therapies designed to address genetic diseases through in vivo and ex vivo gene editing.
