A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing
Summary: The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, ena...
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Elsevier
2018-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718301827 |
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doaj-f557a3a18840449b89062013d6e1f3ec2020-11-25T02:41:57ZengElsevierCell Reports2211-12472018-02-0122922272235A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome EditingJonathan D. Finn0Amy Rhoden Smith1Mihir C. Patel2Lucinda Shaw3Madeleine R. Youniss4Jane van Heteren5Tanner Dirstine6Corey Ciullo7Reynald Lescarbeau8Jessica Seitzer9Ruchi R. Shah10Aalok Shah11Dandan Ling12Jacqueline Growe13Melissa Pink14Ellen Rohde15Kristy M. Wood16William E. Salomon17William F. Harrington18Christian Dombrowski19Walter R. Strapps20Yong Chang21David V. Morrissey22Intellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USAIntellia Therapeutics, Cambridge, MA 02139, USA; Corresponding authorSummary: The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform. : Finn et al. describe the development of a transient, biodegradable LNP-based CRISPR/Cas9 delivery system that achieves >97% knockdown of serum TTR levels following a single administration. Editing levels were stable for 12 months, despite the transient nature of the delivery system and the editing components. Keywords: CRISPR, Cas9, genome editing, LNP, lipid nanoparticle, TTR, CRISPR/Cas9, liver delivery, gene therapy, sgRNAhttp://www.sciencedirect.com/science/article/pii/S2211124718301827 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Jonathan D. Finn Amy Rhoden Smith Mihir C. Patel Lucinda Shaw Madeleine R. Youniss Jane van Heteren Tanner Dirstine Corey Ciullo Reynald Lescarbeau Jessica Seitzer Ruchi R. Shah Aalok Shah Dandan Ling Jacqueline Growe Melissa Pink Ellen Rohde Kristy M. Wood William E. Salomon William F. Harrington Christian Dombrowski Walter R. Strapps Yong Chang David V. Morrissey |
| spellingShingle |
Jonathan D. Finn Amy Rhoden Smith Mihir C. Patel Lucinda Shaw Madeleine R. Youniss Jane van Heteren Tanner Dirstine Corey Ciullo Reynald Lescarbeau Jessica Seitzer Ruchi R. Shah Aalok Shah Dandan Ling Jacqueline Growe Melissa Pink Ellen Rohde Kristy M. Wood William E. Salomon William F. Harrington Christian Dombrowski Walter R. Strapps Yong Chang David V. Morrissey A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing Cell Reports |
| author_facet |
Jonathan D. Finn Amy Rhoden Smith Mihir C. Patel Lucinda Shaw Madeleine R. Youniss Jane van Heteren Tanner Dirstine Corey Ciullo Reynald Lescarbeau Jessica Seitzer Ruchi R. Shah Aalok Shah Dandan Ling Jacqueline Growe Melissa Pink Ellen Rohde Kristy M. Wood William E. Salomon William F. Harrington Christian Dombrowski Walter R. Strapps Yong Chang David V. Morrissey |
| author_sort |
Jonathan D. Finn |
| title |
A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing |
| title_short |
A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing |
| title_full |
A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing |
| title_fullStr |
A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing |
| title_full_unstemmed |
A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing |
| title_sort |
single administration of crispr/cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2018-02-01 |
| description |
Summary: The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform. : Finn et al. describe the development of a transient, biodegradable LNP-based CRISPR/Cas9 delivery system that achieves >97% knockdown of serum TTR levels following a single administration. Editing levels were stable for 12 months, despite the transient nature of the delivery system and the editing components. Keywords: CRISPR, Cas9, genome editing, LNP, lipid nanoparticle, TTR, CRISPR/Cas9, liver delivery, gene therapy, sgRNA |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124718301827 |
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