|
| Status |
Public on Apr 13, 2021 |
| Title |
In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [RNA-seq] |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Other
Expression profiling by high throughput sequencing
|
| Summary |
The majority of known pathogenic point mutations in the human genome are C•G to T•A substitutions. Adenine base editors (ABEs), comprised of nuclease-impaired Cas9 fused to adenine deaminases, enable direct repair of these mutations, making them promising tools for precision in vivo genome editing therapies. However, prior to application in patients, thorough safety and efficacy studies in relevant model organisms are needed. Here, we apply adenine base editing in vivo in the liver of mice and cynomolgus macaques to install a splice site mutation in PCSK9 and reduce blood low-density lipoprotein (LDL) levels, a well-known risk factor for cardiovascular disease. Intravenous delivery of ABE-encoding mRNA and a locus-specific single guide (sg)RNA utilizing lipid nanoparticle (LNP) technology induce up to 67% editing in the liver of mice and up to 34% editing in the liver of macaques, leading to a reduction of plasma PCSK9 and LDL levels. We observed rapid clearance of ABE mRNA after LNP-mediated delivery, and neither sgRNA-dependent nor sgRNA-independent off-target mutations are detected in genomic DNA. Together, our findings support safety and feasibility of adenine base editing to treat patients with monogenetic liver diseases.
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| |
|
| Overall design |
total RNA-seq data from >=3 replicates each
|
| |
|
| Contributor(s) |
Rothgangl TT, Schwank GG |
| Citation(s) |
34012094 |
| |
| Submission date |
Mar 05, 2021 |
| Last update date |
Jul 13, 2021 |
| Contact name |
Tanja Rothgangl |
| E-mail(s) |
tanja.rothgangl@uzh.ch
|
| Organization name |
UZH Zurich
|
| Department |
Pharmacology and Toxicology
|
| Lab |
Schwank
|
| Street address |
Winterthurerstrasse, 190
|
| City |
Zurich |
| ZIP/Postal code |
8057 |
| Country |
Switzerland |
| |
|
| Platforms (2) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (22)
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| This SubSeries is part of SuperSeries: |
| GSE168365 |
In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels |
|
| Relations |
| BioProject |
PRJNA707032 |
| SRA |
SRP309491 |
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