Heavily and fully modified RNAs guide efficient SpyCas9-mediated genome editing

Aamir Mir, Julia F. Alterman, Matthew R. Hassler, Alexandre J. Debacker, Edward Hudgens, Dimas Echeverria, Michael H. Brodsky, Anastasia Khvorova (), Jonathan K. Watts () and Erik J. Sontheimer ()
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Aamir Mir: University of Massachusetts Medical School
Julia F. Alterman: University of Massachusetts Medical School
Matthew R. Hassler: University of Massachusetts Medical School
Alexandre J. Debacker: University of Massachusetts Medical School
Edward Hudgens: University of Massachusetts Medical School
Dimas Echeverria: University of Massachusetts Medical School
Michael H. Brodsky: University of Massachusetts Medical School
Anastasia Khvorova: University of Massachusetts Medical School
Jonathan K. Watts: University of Massachusetts Medical School
Erik J. Sontheimer: University of Massachusetts Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract RNA-based drugs depend on chemical modifications to increase potency and to decrease immunogenicity in vivo. Chemical modification will likely improve the guide RNAs involved in CRISPR-Cas9-based therapeutics as well. Cas9 orthologs are RNA-guided microbial effectors that cleave DNA. Here, we explore chemical modifications at all positions of the crRNA guide and tracrRNA cofactor. We identify several heavily modified versions of crRNA and tracrRNA that are more potent than their unmodified counterparts. In addition, we describe fully chemically modified crRNAs and tracrRNAs (containing no 2′-OH groups) that are functional in human cells. These designs will contribute to Cas9-based therapeutics since heavily modified RNAs tend to be more stable in vivo (thus increasing potency). We anticipate that our designs will improve the use of Cas9 via RNP and mRNA delivery for in vivo and ex vivo purposes.

Date: 2018
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DOI: 10.1038/s41467-018-05073-z

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