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

Vora, Suhani ; Cheng, Jenny ; Xiao, Ru ; VanDusen, Nathan J. ; Quintino, Luis LU orcid ; Pu, William T. ; Vandenberghe, Luk H. ; Chavez, Alejandro and Church, George (2018)
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... (More)
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. (Less)
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publishing date
type
Working paper/Preprint
publication status
published
subject
publisher
bioRxiv
DOI
10.1101/298620
language
English
LU publication?
yes
id
42e217cb-2f2e-48a6-948d-0d9e37674dfd
date added to LUP
2022-03-02 07:53:01
date last changed
2022-03-02 07:53:01
@misc{42e217cb-2f2e-48a6-948d-0d9e37674dfd,
  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.}},
  author       = {{Vora, Suhani and Cheng, Jenny and Xiao, Ru and VanDusen, Nathan J. and Quintino, Luis and Pu, William T. and Vandenberghe, Luk H. and Chavez, Alejandro and Church, George}},
  language     = {{eng}},
  month        = {{01}},
  note         = {{Preprint}},
  publisher    = {{bioRxiv}},
  title        = {{Rational design of a compact CRISPR-Cas9 activator for AAV-mediated delivery}},
  url          = {{http://dx.doi.org/10.1101/298620}},
  doi          = {{10.1101/298620}},
  year         = {{2018}},
}