Metagenomi Announces Publication of Data in Nature Communications Describing Novel, Ultra-Small Nucleases for Gene Editing

Metagenomi Announces Publication of Data in Nature Communications Describing Novel, Ultra-Small Nucleases for Gene Editing




Metagenomi Announces Publication of Data in Nature Communications Describing Novel, Ultra-Small Nucleases for Gene Editing

Newly characterized nucleases are ultra-small with broad targeting potential and translatability, suggesting utility for a variety of genome editing and therapeutic applications

Metagenomi researchers found enzymes capable of genome editing in mammalian cells with >90% efficiency and also identified the smallest adenine base editor to date

EMERYVILLE, Calif.–(BUSINESS WIRE)–Metagenomi, a genetic medicines company with a versatile portfolio of wholly owned, next-generation gene editing tools, today announced the publication of data in Nature Communications describing novel, compact RNA-guided nucleases used to develop the smallest adenine base editor to date. These nucleases are highly active and have broad targeting potential to enable a variety of genome editing and therapeutic applications. The nucleases were uncovered and characterized by Metagenomi researchers, who mined the company’s extensive, proprietary genome-resolved metagenomics database and rapidly developed them into gene editing systems.

In the publication, Metagenomi researchers describe that Cas9d, a new CRISPR type II subtype, contains Zinc-finger motifs and high arginine content – features that are also found in nucleases related to HEARO effectors (HNH Endonuclease-Associated RNA and open reading frames; HNH is a family of nuclease-associated proteins). Metagenomi confirmed that Cas9d and HEARO enzymes have high specificity and targetability due to their associated guide RNAs. Because of the unique biochemical attributes of these systems, Metagenomi refers to them as SMART (SMall Arginine-Rich sysTems). The researchers also sought to determine whether Cas9d and HEARO enzymes can be used as base editors. Results show that both systems can be engineered into a nickase and used for base editing. At only 623 amino acids in size, the adenine base editor developed from a HEARO nickase (MG35-1) is the smallest adenine base editor to date with activity demonstrated in cells.

“Metagenomi’s success in discovering these enzymes and converting them into precision gene editing tools is a victory of science and scalability enabled by our highly differentiated platform,” said Brian C. Thomas, Ph.D., founder and chief executive officer of Metagenomi. “Our proprietary algorithms and high-throughput screening and engineering combine to translate naturally optimized genomic systems into potentially curative therapies for human disease.”

Among Metagenomi’s discoveries, researchers also demonstrated that unoptimized Cas9d enzymes are capable of genome editing in mammalian cells with >90% efficiency. The company has engineered two Cas9d-derived base editors, ABE-MG34-1 and CBE-MG34-1, which edited target loci in E. coli at levels comparable to SpCas9 base editors. Metagenomi’s is the smallest base editor known to-date that is active in both E. coli and mammalian cells that are engineered from a nickase.

Traditional genome editing systems pose a challenge for therapeutic delivery due to their large size. Metagenomi sought to identify and biochemically characterize ultra-small systems that are distantly related to those that have been previously described. “If we want to expand the therapeutic application of programmable, RNA-guided nucleases for biotechnological applications, there is a need for targetable systems that are small enough to be delivered efficiently,” highlighted Christopher Brown, Ph.D., senior director of discovery at Metagenomi, and a study author. “For the novel CRISPR and HEARO nucleases that we researched, we demonstrated efficient activity in vitro and in cells, and further engineered ultra-small base editors that bring us closer to enabling next-generation therapeutic applications to treat genetic diseases.”

To learn more about Metagenomi’s pipeline, please visit: https://metagenomi.co/pipeline/.

About Metagenomi

Metagenomi is a gene editing company committed to developing potentially curative therapeutics by leveraging a proprietary toolbox of next-generation gene editing systems to accurately edit DNA where current technologies cannot. Our metagenomics-powered discovery platform and analytical expertise reveal novel cellular machinery sourced from otherwise unknown organisms. We adapt and forge these naturally evolved systems into powerful gene editing systems that are ultra-small, extremely efficient, highly specific and have a decreased risk of immune response. These systems fuel our pipeline of novel medicines and can be leveraged by partners. Our goal is to revolutionize gene editing for the benefit of patients around the world. For more information, please visit https://metagenomi.co/.

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