A Novel “Mini-CRISPR” Could Be More Successful at Editing the Dystrophin Gene

A study conducted by Mammoth Biosciences has revealed that the mini-CRISPR gene editing method, also called NanoCas, is more effective in treating Duchenne Muscular Dystrophy (DMD).

Several research groups have been attempting to create compact CRISPR systems that can fit into a single AAV vector while maintaining editing capabilities. The group at Mammoth Biosciences is one of these; they might have found success. Its researchers started by sorting through genetic sequence information from several CRISPR types that are found in microorganisms.

Lucas Harrington, the company’s chief scientific officer and co-founder and a former Doudna student, claims that after putting an initial 176 applicants through “a barrage of tests,” they discovered “that needle in the haystack.” That best choice was given the name NanoCas; at 425 amino acids, it is roughly one-third longer than Cas9. It was designed by Harrington and his associates to efficiently cut mammalian DNA.

Key takeaways from the NanoCas study include:

  • Editing efficiency matches that of first-generation CRISPR systems: When targeting the PCSK9 gene in mouse liver in vivo, NanoCas showed saturating editing efficiencies of approximately 60%, on par with that of SaCas9, which is about three-fold larger in size. Both CRISPR systems reduced serum PCSK9 protein to undetectable levels.
  • Robust single AAV editing across multiple muscle tissues: NanoCas demonstrated 10% to 40% editing of the dystrophin gene across the quadricep, calf and heart muscle in a humanized mouse model of Duchenne Muscular Dystrophy (DMD), when delivered via a single AAV vector.
  • First demonstration of single AAV muscle editing in non-human primates: NanoCas achieved in vivo editing efficiencies of up to 30% when targeting dystrophin in the skeletal muscle of cynomolgus macaques. NanoCas also showed 15% editing across the heart, compared to 10% with SaCas9. Analysis of liver tissue showed minimal off-target editing.
SourceScience

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