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dc.contributor.author
Villiger, Lukas
dc.contributor.author
Rothgangl, Tanja
dc.contributor.author
Witzigmann, Dominik
dc.contributor.author
Oka, Rurika
dc.contributor.author
Lin, Paulo J.C.
dc.contributor.author
Qi, Weihong
dc.contributor.author
Janjuha, Sharan
dc.contributor.author
Berk, Christian
dc.contributor.author
Ringnalda, Femke
dc.contributor.author
Beattie, Mitchell B.
dc.contributor.author
Stoffel, Markus
dc.contributor.author
Thöny, Beat
dc.contributor.author
Hall, Jonathan
dc.contributor.author
Rehrauer, Hubert
dc.contributor.author
van Boxtel, Ruben
dc.contributor.author
Tam, Ying K.
dc.contributor.author
Schwank, Gerald
dc.date.accessioned
2021-03-05T14:25:03Z
dc.date.available
2021-01-13T14:36:34Z
dc.date.available
2021-01-14T15:11:58Z
dc.date.available
2021-01-26T12:26:17Z
dc.date.available
2021-03-05T14:25:03Z
dc.date.issued
2021-02
dc.identifier.issn
2157-846X
dc.identifier.other
10.1038/s41551-020-00671-z
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/462202
dc.description.abstract
Base editors are RNA-programmable deaminases that enable precise single-base conversions in genomic DNA. However, off-target activity is a concern in the potential use of base editors to treat genetic diseases. Here, we report unbiased analyses of transcriptome-wide and genome-wide off-target modifications effected by cytidine base editors in the liver of mice with phenylketonuria. The intravenous delivery of intein-split cytidine base editors by dual adeno-associated viruses led to the repair of the disease-causing mutation without generating off-target mutations in the RNA and DNA of the hepatocytes. Moreover, the transient expression of a cytidine base editor mRNA and a relevant single-guide RNA intravenously delivered by lipid nanoparticles led to ~21% on-target editing and to the reversal of the disease phenotype; there were also no detectable transcriptome-wide and genome-wide off-target edits. Our findings support the feasibility of therapeutic cytidine base editing to treat genetic liver diseases.
en_US
dc.language.iso
en
en_US
dc.publisher
Nature Publishing Group
en_US
dc.subject
Genetic engineering
en_US
dc.subject
Targeted gene repair
en_US
dc.title
In vivo cytidine base editing of hepatocytes without detectable off-target mutations in RNA and DNA
en_US
dc.title.alternative
Transient in vivo genome base editing enables curative treatment of a monogenic liver disorder without generating substantial RNA- and DNA off-target mutations
en_US
dc.type
Journal Article
dc.date.published
2021-01-25
ethz.journal.title
Nature Biomedical Engineering
ethz.journal.volume
5
en_US
ethz.journal.issue
2
en_US
ethz.journal.abbreviated
Nat Biomed Eng
ethz.pages.start
179
en_US
ethz.pages.end
189
en_US
ethz.grant
Establishment of in vivo CRISPR-Cas base editor approaches to treat monogenetic liver diseases
en_US
ethz.grant
Chemical Approaches to Functionalize Human microRNAs
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02539 - Institut für Molecular Health Sciences / Institute of Molecular Health Sciences::03739 - Stoffel, Markus / Stoffel, Markus
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02539 - Institut für Molecular Health Sciences / Institute of Molecular Health Sciences::09492 - Schwank, Gerald (ehemalig) / Schwank, Gerald (former)
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00022 - Bereich VP Forschung / Domain VP Research::02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03760 - Hall, Jonathan / Hall, Jonathan
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02539 - Institut für Molecular Health Sciences / Institute of Molecular Health Sciences::03739 - Stoffel, Markus / Stoffel, Markus
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02539 - Institut für Molecular Health Sciences / Institute of Molecular Health Sciences::09492 - Schwank, Gerald (ehemalig) / Schwank, Gerald (former)
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00022 - Bereich VP Forschung / Domain VP Research::02207 - Functional Genomics Center Zurich / Functional Genomics Center Zurich
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03760 - Hall, Jonathan / Hall, Jonathan
ethz.grant.agreementno
185293
ethz.grant.agreementno
169612
ethz.grant.fundername
SNF
ethz.grant.fundername
SNF
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.program
Projektförderung in Biologie und Medizin (Abteilung III)
ethz.grant.program
Projektförderung in Mathematik, Natur- und Ingenieurwissenschaften (Abteilung II)
ethz.date.deposited
2021-01-13T14:36:43Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2021-03-05T14:25:26Z
ethz.rosetta.lastUpdated
2021-03-05T14:25:26Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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