Engineered Cas12i2 is a versatile high-efficiency platform for therapeutic genome editing

Colin McGaw, Anthony J. Garrity, Gabrielle Z. Munoz, Jeffrey R. Haswell, Sejuti Sengupta, Elise Keston-Smith, Pratyusha Hunnewell, Alexa Ornstein, Mishti Bose, Quinton Wessells, Noah Jakimo, Paul Yan, Huaibin Zhang, Lauren E. Alfonse, Roy Ziblat, Jason M. Carte, Wei-Cheng Lu, Derek Cerchione, Brendan Hilbert, Shanmugapriya Sothiselvam, Winston X. Yan, David R. Cheng, David A. Scott, Tia DiTommaso () and Shaorong Chong
Additional contact information
Colin McGaw: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Anthony J. Garrity: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Gabrielle Z. Munoz: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Jeffrey R. Haswell: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Sejuti Sengupta: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Elise Keston-Smith: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Pratyusha Hunnewell: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Alexa Ornstein: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Mishti Bose: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Quinton Wessells: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Noah Jakimo: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Paul Yan: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Huaibin Zhang: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Lauren E. Alfonse: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Roy Ziblat: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Jason M. Carte: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Wei-Cheng Lu: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Derek Cerchione: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Brendan Hilbert: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Shanmugapriya Sothiselvam: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Winston X. Yan: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
David R. Cheng: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
David A. Scott: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Tia DiTommaso: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500
Shaorong Chong: Arbor Biotechnologies, 20 Acorn Park Drive, Tower 500

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract The CRISPR-Cas type V-I is a family of Cas12i-containing programmable nuclease systems guided by a short crRNA without requirement for a tracrRNA. Here we present an engineered Type V-I CRISPR system (Cas12i), ABR-001, which utilizes a tracr-less guide RNA. The compact Cas12i effector is capable of self-processing pre-crRNA and cleaving dsDNA targets, which facilitates versatile delivery options and multiplexing, respectively. We apply an unbiased mutational scanning approach to enhance initially low editing activity of Cas12i2. The engineered variant, ABR-001, exhibits broad genome editing capability in human cell lines, primary T cells, and CD34+ hematopoietic stem and progenitor cells, with both robust efficiency and high specificity. In addition, ABR-001 achieves a high level of genome editing when delivered via AAV vector to HEK293T cells. This work establishes ABR-001 as a versatile, specific, and high-performance platform for ex vivo and in vivo gene therapy.

Date: 2022
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DOI: 10.1038/s41467-022-30465-7

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