The dirty secret of CRISPR therapeutics: most of the famous nucleases are too big for the best delivery vehicle we have.
Cas9 from S. pyogenes is around 1,368 amino acids. Add a guide RNA, regulatory elements, and a polyA tail, and you’re well past the 4.7 kb cargo limit of an AAV vector. The whole field has spent a decade working around this.
Splitting Cas9 across two AAVs.
Using larger lipid nanoparticles.
Scrunching down to smaller orthologs like SaCas9 or compact Cas12f variants.
Cas12f systems are particularly interesting because they’re tiny, often under 600 amino acids. The catch: most of them barely edit. The compact size comes with a steep activity penalty. Researchers have been engineering them for years trying to bridge the gap.
Metagenomi just published a paper in Nature Structural & Molecular Biology on MG119-28, an engineered Cas12f variant (originally Al3Cas12f) that’s (max) 488 amino acids in length and edits across multiple human genomic loci with what they describe as substantially improved activity over prior compact systems.
488 amino acids. That’s a headline in and of itself.
CRISPR nuclease size comparison (amino acids)
1,368 aa
1,053 aa
488 aa
AAV cargo limit: ~4.7 kb. Smaller nuclease = more room for guide RNA, promoters, regulatory elements.
To put that in context, an MG119-28 plus its guide RNA can fit comfortably inside a single AAV with room left over for promoters, terminators, and even some tissue-specific regulatory elements.
That single-vector capability is the unlock for in vivo therapeutic editing in tissues where lipid nanoparticles don’t reach well, like CNS, muscle, and retina.
This isn’t a side project for Metagenomi.
The company’s entire thesis is built on mining environmental microbial DNA for CRISPR systems that conventional discovery missed. Their database has over 11 billion proteins and roughly 5,000 CRISPR loci from organisms that have never been cultured.
They’re running generative AI models trained on natural diversity to design compact, low-immunogenicity editors.
MG119-28 is the second compact system from their pipeline to make headlines.
The first was MG21-1, a 1,098-amino-acid type II nuclease that they showed could be packaged with its guide RNA in a single AAV.
The Biotech Voyager
Early-stage biotech signals, personalized.
The signals that matter to you, contextualized and written directly to you, so you cut through the noise and immediately understand why it matters.
The competitive picture here is worth understanding too.
Editas, Intellia, and Beam Therapeutics are a few examples of biotechs working on next-generation editors with various flavors of compact and modified Cas systems.
Editas has its AsCas12a variant.
Beam uses base editors built on Cas9 frameworks.
Intellia is moving with optimized SpCas9 platforms.
What Metagenomi has that’s genuinely differentiated is the discovery engine.
Most editing companies engineer one or two enzymes. Metagenomi keeps pulling new ones out of the metagenomic database.
MG119-28 is the latest evidence that this approach works.
The company’s lead therapeutic program, MGX-001 for hemophilia A, is a different beast (it uses a larger nuclease and is targeted at the liver). But the MG119-28 publication signals where the platform is headed: in vivo editing in tissues that haven’t been reachable.
For context on what compact CRISPR systems are unlocking elsewhere, see SNIPR Biome’s phage-delivered CRISPR antibiotic and Tacit Therapeutics’ RNA splicing approach, which is taking a completely different angle on the same delivery problem.
The paper is published.
The platform is producing.
The next milestone for Metagenomi is whether MG119-28 (or one of its siblings) shows up in a development candidate program for an extrahepatic indication.
That’s the test.
