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Treatment of Genetic Diseases With CRISPR Genome Editing

To identify the key insights or developments described in this article
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In nature, microorganisms use CRISPR (clustered regularly interspaced palindromic repeats) and CRISPR-associated (Cas) proteins for antiviral immunity through recognition and destruction of specific DNA sequences. Over the past decade, CRISPR genome editing has been developed to create transformative technologies to treat, cure, and prevent human disease.

CRISPR genome editing allows scientists to change DNA sequences in cells at virtually any desired position, enabling both fundamental research and therapeutic applications (Figure). CRISPR-Cas9, the most widely used genome editor, is an RNA-guided DNA-cutting enzyme that makes double-stranded DNA breaks at preselected (on-target) positions in the DNA of living cells.1 Repair of the break site results in either small insertions and deletions (indels) introduced by error-prone repair or insertion of a new DNA donor sequence chosen by the investigator (homology-directed repair). Indels are useful for interrupting gene function, whereas sequence insertion can replace a defective sequence to restore gene function.2 In either case, controlling the exact editing outcome for a particular indication in a specific cell type or organ is challenging, and unintended (off-target) DNA changes can be harmful.

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Article Information

Corresponding Author: Jennifer A. Doudna, PhD, 2151 Berkeley Way, Berkeley, CA 94704 (doudna@berkeley.edu).

Conflict of Interest Disclosures: Dr Kan reported being a fellow in the Pediatric Scientist Development Program, supported by award K12-HD000850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Doudna reported being a cofounder of Caribou Biosciences, Editas Medicine, Scribe Therapeutics, Intellia Therapeutics, and Mammoth Biosciences; serving as a scientific advisory board member for Caribou Biosciences, Intellia Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics, Mammoth Biosciences, Synthego, Algen Biotechnologies, Felix Biosciences, and Inari; being a director at Johnson & Johnson; and having research projects sponsored by Biogen, Pfizer, AppleTree Partners, and Roche. In addition, Dr Doudna had a patent for CRISPR-Cas9 issued.

References
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Stark  JM , Pierce  AJ , Oh  J ,  et al.  Genetic steps of mammalian homologous repair with distinct mutagenic consequences.   Mol Cell Biol. 2004;24(21):9305-9316. PubMedGoogle ScholarCrossref
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Komor  AC , Kim  YB , Packer  MS ,  et al.  Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage.   Nature. 2016;533(7603):420-424. doi:10.1038/nature17946PubMedGoogle ScholarCrossref
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Anzalone  AV , Randolph  PB , Davis  JR ,  et al.  Search-and-replace genome editing without double-strand breaks or donor DNA.   Nature. 2019;576(7785):149-157. doi:10.1038/s41586-019-1711-4PubMedGoogle ScholarCrossref
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Pickar-Oliver  A , Gersbach  CA .  The next generation of CRISPR-Cas technologies and applications.   Nat Rev Mol Cell Biol. 2019;20(8):490-507. doi:10.1038/s41580-019-0131-5PubMedGoogle ScholarCrossref
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Locatelli F, Frangoul H, Corbacioglu S, et al.  Efficacy and safety of a single dose of CTX001 for transfusion-dependent beta-thalassemia and severe sickle cell disease. June 12, 2022. https://bit.ly/3Ak5Ao4
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Stadtmauer  EA , Fraietta  JA , Davis  MM ,  et al.  CRISPR-engineered T cells in patients with refractory cancer.   Science. 2020;367(6481):eaba7365. doi:10.1126/science.aba7365PubMedGoogle ScholarCrossref
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Intellia and Regeneron present updated interim data from phase 1 study of CRISPR-based NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis demonstrating that deep serum TTR reductions remained durable after a single dose. June 24, 2022. https://ir.intelliatx.com/news-releases/news-release-details/intellia-and-regeneron-present-updated-interim-data-phase-1
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