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Rational design of a compact CRISPR-Cas9 activator for AAV-mediated delivery

View ORCID ProfileSuhani Vora, Jenny Cheng, Ru Xiao, Nathan J. VanDusen, Luis Quintino, William T. Pu, Luk H. Vandenberghe, Alejandro Chavez, George Church
doi: https://doi.org/10.1101/298620
Suhani Vora
1Wyss Institute for Biologically Inspired Engineering
2MIT Department of Biological Engineering
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  • ORCID record for Suhani Vora
Jenny Cheng
1Wyss Institute for Biologically Inspired Engineering
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Ru Xiao
3Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary
10Department of Ophthalmology, Harvard Medical School
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Nathan J. VanDusen
4Department of Cardiology, Boston Children’s Hospital
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Luis Quintino
5Department of Experimental Medical Science, Lund University
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William T. Pu
4Department of Cardiology, Boston Children’s Hospital
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Luk H. Vandenberghe
3Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary
9The Broad Institute of Harvard and MIT
10Department of Ophthalmology, Harvard Medical School
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Alejandro Chavez
1Wyss Institute for Biologically Inspired Engineering
6Department of Pathology and Cell Biology, Columbia University
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George Church
1Wyss Institute for Biologically Inspired Engineering
7Harvard Medical School, Department of Genetics
8Harvard-MIT, Health Sciences and Technology
9The Broad Institute of Harvard and MIT
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Abstract

Akin to Zinc Finger and Transcription Activator Like Effector based transcriptional modulators, nuclease-null CRISPR-Cas9 provides a groundbreaking programmable DNA binding platform, begetting an arsenal of targetable regulators for transcriptional and epigenetic perturbation, by either directly tethering, or recruiting, transcription enhancing effectors to either component of the Cas9/guide RNA complex. Application of these programmable regulators is now gaining traction for the modulation of disease-causing genes or activation of therapeutic genes, in vivo. Adeno-Associated Virus (AAV) is an optimal delivery vehicle for in vivo delivery of such regulators to adult somatic tissue, due to the efficacy of viral delivery with minimal concerns about immunogenicity or integration. However, present Cas9 activator systems are notably beyond the packaging capacity of a single AAV delivery vector capsid. Here, we engineer a compact CRISPR-Cas9 activator for convenient AAV-mediated delivery. We validate efficacy of the CRISPR-Cas9 transcriptional activation using AAV delivery in several cell lines.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 15, 2018.
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Rational design of a compact CRISPR-Cas9 activator for AAV-mediated delivery
Suhani Vora, Jenny Cheng, Ru Xiao, Nathan J. VanDusen, Luis Quintino, William T. Pu, Luk H. Vandenberghe, Alejandro Chavez, George Church
bioRxiv 298620; doi: https://doi.org/10.1101/298620
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Rational design of a compact CRISPR-Cas9 activator for AAV-mediated delivery
Suhani Vora, Jenny Cheng, Ru Xiao, Nathan J. VanDusen, Luis Quintino, William T. Pu, Luk H. Vandenberghe, Alejandro Chavez, George Church
bioRxiv 298620; doi: https://doi.org/10.1101/298620

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