AsCas12a ultra nuclease facilitates the rapid generation of therapeutic cell medicines

Liyang Zhang, John A. Zuris, Ramya Viswanathan, Jasmine N. Edelstein, Rolf Turk, Bernice Thommandru, H. Tomas Rube, Steve E. Glenn, Michael A. Collingwood, Nicole M. Bode, Sarah F. Beaudoin, Swarali Lele, Sean N. Scott, Kevin M. Wasko, Steven Sexton, Christopher M. Borges, Mollie S. Schubert, Gavin L. Kurgan, Matthew S. McNeill, Cecilia A. Fernandez, Vic E. Myer, Richard A. Morgan, Mark A. Behlke () and Christopher A. Vakulskas ()
Additional contact information
Liyang Zhang: Integrated DNA Technologies, Inc
John A. Zuris: Editas Medicine Inc, 11 Hurley St
Ramya Viswanathan: Editas Medicine Inc, 11 Hurley St
Jasmine N. Edelstein: Editas Medicine Inc, 11 Hurley St
Rolf Turk: Integrated DNA Technologies, Inc
Bernice Thommandru: Integrated DNA Technologies, Inc
H. Tomas Rube: University of California - Merced, 5200 Lake Rd
Steve E. Glenn: Integrated DNA Technologies, Inc
Michael A. Collingwood: Integrated DNA Technologies, Inc
Nicole M. Bode: Integrated DNA Technologies, Inc
Sarah F. Beaudoin: Integrated DNA Technologies, Inc
Swarali Lele: Editas Medicine Inc, 11 Hurley St
Sean N. Scott: Editas Medicine Inc, 11 Hurley St
Kevin M. Wasko: Editas Medicine Inc, 11 Hurley St
Steven Sexton: Editas Medicine Inc, 11 Hurley St
Christopher M. Borges: Editas Medicine Inc, 11 Hurley St
Mollie S. Schubert: Integrated DNA Technologies, Inc
Gavin L. Kurgan: Integrated DNA Technologies, Inc
Matthew S. McNeill: Integrated DNA Technologies, Inc
Cecilia A. Fernandez: Editas Medicine Inc, 11 Hurley St
Vic E. Myer: Editas Medicine Inc, 11 Hurley St
Richard A. Morgan: Editas Medicine Inc, 11 Hurley St
Mark A. Behlke: Integrated DNA Technologies, Inc
Christopher A. Vakulskas: Integrated DNA Technologies, Inc

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Though AsCas12a fills a crucial gap in the current genome editing toolbox, it exhibits relatively poor editing efficiency, restricting its overall utility. Here we isolate an engineered variant, “AsCas12a Ultra”, that increased editing efficiency to nearly 100% at all sites examined in HSPCs, iPSCs, T cells, and NK cells. We show that AsCas12a Ultra maintains high on-target specificity thereby mitigating the risk for off-target editing and making it ideal for complex therapeutic genome editing applications. We achieved simultaneous targeting of three clinically relevant genes in T cells at >90% efficiency and demonstrated transgene knock-in efficiencies of up to 60%. We demonstrate site-specific knock-in of a CAR in NK cells, which afforded enhanced anti-tumor NK cell recognition, potentially enabling the next generation of allogeneic cell-based therapies in oncology. AsCas12a Ultra is an advanced CRISPR nuclease with significant advantages in basic research and in the production of gene edited cell medicines.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24017-8

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DOI: 10.1038/s41467-021-24017-8

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