Chemical engineering of CRISPR–Cas systems for therapeutic application

Halle M. Barber, Adrian A. Pater, Keith T. Gagnon, Masad J. Damha, Daniel O’Reilly

Research output: Contribution to journalReview articlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere1481
JournalNature Reviews Drug Discovery
DOIs
StateAccepted/In press - 2024

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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