TY - JOUR
T1 - Chemical engineering of CRISPR–Cas systems for therapeutic application
AU - Barber, Halle M.
AU - Pater, Adrian A.
AU - Gagnon, Keith T.
AU - Damha, Masad J.
AU - O’Reilly, Daniel
N1 - Publisher Copyright:
© Springer Nature Limited 2024.
PY - 2024
Y1 - 2024
N2 - Clustered regularly interspaced short palindromic repeats (CRISPR) technology has transformed molecular biology and the future of gene-targeted therapeutics. CRISPR systems comprise a CRISPR-associated (Cas) endonuclease and a guide RNA (gRNA) that can be programmed to guide sequence-specific binding, cleavage, or modification of complementary DNA or RNA. However, the application of CRISPR-based therapeutics is challenged by factors such as molecular size, prokaryotic or phage origins, and an essential gRNA cofactor requirement, which impact efficacy, delivery and safety. This Review focuses on chemical modification and engineering approaches for gRNAs to enhance or enable CRISPR-based therapeutics, emphasizing Cas9 and Cas12a as therapeutic paradigms. Issues that chemically modified gRNAs seek to address, including drug delivery, physiological stability, editing efficiency and off-target effects, as well as challenges that remain, are discussed.
AB - Clustered regularly interspaced short palindromic repeats (CRISPR) technology has transformed molecular biology and the future of gene-targeted therapeutics. CRISPR systems comprise a CRISPR-associated (Cas) endonuclease and a guide RNA (gRNA) that can be programmed to guide sequence-specific binding, cleavage, or modification of complementary DNA or RNA. However, the application of CRISPR-based therapeutics is challenged by factors such as molecular size, prokaryotic or phage origins, and an essential gRNA cofactor requirement, which impact efficacy, delivery and safety. This Review focuses on chemical modification and engineering approaches for gRNAs to enhance or enable CRISPR-based therapeutics, emphasizing Cas9 and Cas12a as therapeutic paradigms. Issues that chemically modified gRNAs seek to address, including drug delivery, physiological stability, editing efficiency and off-target effects, as well as challenges that remain, are discussed.
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U2 - 10.1038/s41573-024-01086-0
DO - 10.1038/s41573-024-01086-0
M3 - Review article
C2 - 39690326
AN - SCOPUS:85212277545
SN - 1474-1776
JO - Nature Reviews Drug Discovery
JF - Nature Reviews Drug Discovery
M1 - e1481
ER -