Abstract
CRISPR-based drugs can theoretically manipulate any genetic target. In practice, however, these drugs must enter the desired cell without eliciting an unwanted immune response, so a delivery system is often required. Here, we review drug delivery systems for CRISPR-based genome editors, focusing on adeno-associated viruses and lipid nanoparticles. After describing how these systems are engineered and their subsequent characterization in preclinical animal models, we highlight data from recent clinical trials. Preclinical targeting mediated by polymers, proteins, including virus-like particles, and other vehicles that may deliver CRISPR systems in the future is also discussed.
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Acknowledgements
The authors thank D. Loughrey and K. Tiegren at the Emory University School of Medicine as well as R. Macrae at the Broad Institute for copyediting the manuscript.
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V.M. declares no competing interests. F.Z. is a scientific adviser and cofounder of Editas Medicine, Beam Therapeutics, Pairwise Plants, Arbor Biotechnologies and Proof Diagnostics. F.Z. is also a scientific adviser for Octant. J.E.D. is an adviser to GV.
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Intellia Therapeutics clinical data: https://www.intelliatx.com/wp-content/uploads/PNS-Oral-Pres_Gillmore_062621.pdf
Intellia Therapeutics HAE phase I: https://ir.intelliatx.com/static-files/a57908a6-aaca-404d-9072-32471cd3d41e
Intellia Therapeutics updated interim clinical data: https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-present-updated-interim-clinical-data
Intellia Therapeutics/Regeneron clinical update: https://ir.intelliatx.com/news-releases/news-release-details/intellia-and-regeneron-announce-updated-phase-1-data
Pfizer DMD phase III: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-open-first-us-sites-phase-3-trial-investigational
Sarepta Therapeutics Biologics License Application: https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-submits-biologics-license-application-srp
Sarepta Therapeutics licenses MyoAAV: https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-progress-myoaav-program-and
Solid Biosciences next-generation AAV: https://www.solidbio.com/about/media/news/letter-to-the-duchenne-community-strategic-update
Spark Therapeutics/Pfizer hemophilia B phase III: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-positive-top-line-results-phase-3-study
uniQure hemophilia B phase III: https://www.uniqure.com/assets/uploads/doc/eahad2022-hope-b-oral-presentation-20220204.pdf
Verve Therapeutics doses first patient: https://ir.vervetx.com/news-releases/news-release-details/verve-therapeutics-doses-first-human-investigational-vivo-base
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Madigan, V., Zhang, F. & Dahlman, J.E. Drug delivery systems for CRISPR-based genome editors. Nat Rev Drug Discov 22, 875–894 (2023). https://doi.org/10.1038/s41573-023-00762-x
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DOI: https://doi.org/10.1038/s41573-023-00762-x
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