Mammoth Biosciences, Inc., a biotechnology company harnessing its proprietary next-generation in vivo CRISPR gene editing platform to create potential one-time curative therapies, recently presented new preclinical data on its lead developmental candidate, MB-111, at the American Heart Association Scientific Sessions, held November 6–9 in Chicago.

MB-111 is a potential first-in-class, single-dose in vivo CRISPR therapy designed to durably reduce plasma triglyceride levels in patients with persistent chylomicronemia (PC). MB-111 was developed using CasPhi, an ultracompact CRISPR nuclease that is significantly smaller than Cas9-based systems. Encapsulated and delivered within a lipid nanoparticle along with the guide RNA, MB-111 disrupts the expression of the APOC3 gene, a key regulator of triglyceride metabolism, in the liver.

PC is characterized by severely elevated fasting triglyceride levels (> 1,000 mg/dL) that do not respond sufficiently to standard lipid-lowering agents. Patients face an ongoing risk of recurrent acute pancreatitis, a complication associated with a per-incidence mortality rate between 5% and 30%. While recently available therapies targeting APOC3 have been shown to lower triglycerides, they require repeat administration throughout a patient’s lifetime.

“We are encouraged by the preclinical efficacy and safety data observed to date for MB-111,” said Trevor Martin, Ph.D., co-founder and chief executive officer of Mammoth Biosciences. “Demonstrating sustained reductions in apoC-III and triglycerides in animal models, coupled with a clean safety profile, strengthens the rationale for advancing this program into clinical testing as we work to bring durable in vivo CRISPR therapies to patients living with cardiometabolic diseases.”

Key findings:

  • Robust apoC-III and triglyceride reduction: MB-111 led to dose-dependent reductions of apoC-III protein and serum triglycerides by up to 95% in a humanized transgenic mouse model of severe hypertriglyceridemia.

  • Durability of response: A single intravenous dose of MB-111 at 1 mg/kg and 3 mg/kg achieved saturating editing in liver tissue of non-human primates (NHPs), yielding up to a 90% reduction in APOC3 mRNA and suppression of apoC-III protein for nine months post-treatment.

  • Favorable tolerability and wide therapeutic window: MB-111 was well tolerated in GLP toxicology studies conducted in NHPs. Modest, transient elevations in liver enzymes were observed primarily at higher doses and resolved within one week. The no-observed-adverse-effect level (NOAEL) was established at 2.5 mg/kg, the highest dose evaluated.

  • Highly specific biodistribution and favorable genotoxicity: Minimal editing was observed at the highest evaluated dose of 3mg/kg in NHPs, limited to the adrenal gland, spleen and administration site. No editing was detected in reproductive tissues, and follow-up evaluation showed no germline transmission. No large-scale structural rearrangements or chromosomal instability was observed in primary human hepatocytes.

The poster, titled “CRISPR-Based in vivo Gene Editing Using an Engineered CasPhi Nuclease for Durable Reduction of apoC-III Protein and Triglycerides to Treat Persistent Chylomicronemia” is available on the Mammoth Biosciences website.

About Mammoth Biosciences

Mammoth Biosciences is a biotechnology company focused on leveraging its proprietary ultracompact CRISPR systems to develop potential long-term curative therapies for patients with life-threatening and debilitating diseases. Founded by CRISPR pioneer and Nobel laureate Jennifer Doudna and Trevor Martin, Janice Chen, and Lucas Harrington, the company’s ultracompact systems are designed to be more specific and packageable to enable in vivo gene editing in difficult to reach tissues utilizing both nuclease applications and new editing modalities beyond double stranded breaks, including base editing, reverse transcriptase editing, and epigenetic editing. The company is building out its wholly owned pipeline of potential in vivo gene editing therapeutics and capabilities and has partnerships with leading pharmaceutical and biotechnology companies to broaden the reach of its innovative and proprietary technology platform. Mammoth Biosciences’ deep science and industry experience, along with a robust and differentiated intellectual property portfolio, have enabled the company to further its mission to transform the lives of patients and deliver on the promise of CRISPR technologies.

For more information, please visit www.mammoth.bio or follow Mammoth on LinkedIn or X.

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