Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

2 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Efficient generation of pathogenic A-to-G mutations in human tripronuclear embryos via ABE-mediated base editing

ABSTRACT: Base editing systems show their power in modeling and correcting the pathogenic mutations of genetic diseases. Previous studies have already demonstrated the editing efficiency of BE3-mediated C-to-T conversion in human embryos. However, the precision and efficiency of a recently developed adenine base editors (ABE) which convert A-to-G editing in human embryos remains to be addressed. We efficiently generated pathogenic A-to-G mutations in human tripronuclear embryos via ABE-mediated base editing.

SUBMITTER: Guanglei,Li

PROVIDER: OEX001544 | NODE |

REPOSITORIES: NODE

ACCESS DATA

Json Xml

Publications

Sorry, this publication's infomation has not been loaded in the Indexer, please go directly to PUBMED or Altmetric.

Similar Datasets

A-T to G-C base editing efficiency at targeted gene sites in HEK293T cell line

Project description:A-T to G-C base editing efficiency at targeted gene sites in HEK293T cells using the dCas12f-ABE design or the Cas12f-ABE design. Found that the total A-T to G-C conversion efficiency of Circular gRNAs exhibited about two-fold increase compared with U6 gRNAs. We further analyzed the pattern for A-T to G-C conversion on the target site, and observed that the most efficient base editing occurred in a narrow window A3 (3bp downstream of the PAM) similar to U6 gRNAs. In summary, Circular gRNAs with dCas12f-ABE design could enhance A-T to G-C base editing efficiency in a narrow window.

2024-03-11 | GSE260967 | GEO

In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [amplicon-seq]

Project description: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.

2021-04-13 | GSE168364 | GEO

In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [RNA-seq]

2021-04-13 | GSE168363 | GEO

Base Editing Correction of a Hypertrophic Cardiomyopathy-Causing MYH7 Mutation in Human Cardiomyocytes and Humanized Mice

Project description:The most common form of genetic heart disease is hypertrophic cardiomyopathy (HCM), which is caused by mutations in cardiac sarcomeric genes and leads to abnormal heart muscle thickening. Complications of HCM include heart failure, arrhythmia, and sudden cardiac death. The dominant-negative c.1208 G>A (p.R403Q) mutation in b-myosin (MYH7) is a common and well-studied mutation that leads to increased cardiac contractility and HCM onset. Here we identify an adenine base editor (ABE) and single-guide RNA system that can efficiently correct this human pathogenic mutation with minimal off-target and bystander editing. We show that delivery of base editing components rescues pathological manifestations of HCM in iPSC-cardiomyocytes derived from HCM patients and in a humanized mouse model of HCM. Our findings demonstrate the use of base editing to treat inherited cardiac diseases and prompt the further development of ABE-based therapies to correct a variety of monogenic mutations causing cardiac disease.

2022-10-25 | GSE201755 | GEO

Precise genomic editing of a pathogenic RBM20 mutation rescues dilated cardiomyopathy

Project description:Mutations in RNA binding motif protein 20 (RBM20) are a common cause of dilated cardiomyopathy (DCM). Many RBM20 mutations cluster within an arginine/serine rich (RS-rich) domain, resulting in mis-localization of RBM20 to ribonucleoprotein granules within the cytoplasm, abnormal splicing of cardiac genes, and cardiomyocyte dysfunction. We used adenine base editing (ABE) and prime editing to correct pathogenic p.R634Q and p.R636S mutations in the RS-rich domain in human isogenic induced pluripotent stem cell-derived cardiomyocytes. We also created humanized Rbm20R636Q mutant mice, which succumbed to severe cardiac dysfunction, heart failure and premature death. Systemic delivery of ABE components by adeno-associated virus in these mice restored cardiac function and extended life span. These findings demonstrate the potential of precise correction of genetic mutations as a promising therapeutic approach for DCM.

2022-08-11 | GSE210783 | GEO

Precise genomic editing of a pathogenic RBM20 mutation rescues dilated cardiomyopathy

2022-08-14 | GSE211005 | GEO

Cas12a base editors induce efficient and specific editing with low DNA damage response (DNA targeted sequencing)

Project description:The advent of base editors (BEs) holds a promising potential in correcting pathogenic-related point mutations to treat relevant diseases. Unexpectedly, Cas9 nickase (nCas9) derived BEs lead to DNA double-strand breaks, which can trigger unwanted cellular responses including a p53-mediated DNA damage response (DDR). Here, we showed that catalytically-dead-Cas12a (dCas12a) conjugated BEs induced no DNA break and minimally activated DDR proteins including H2AX, ATM, ATR and p53. We further developed a BEACON (Base Editing induced by human APOBEC3A and Cas12a without DNA break) system that fuses dCas12a to the engineered APOBEC3A with enhanced deamination efficiency and editing specificity. By using BEACON, efficient C-to-T editing was achieved at levels comparable to AncBE4max and only low levels of DDR and RNA off-target (OT) effects were triggered in mammalian cells. BEACON also induced in vivo base editing in mouse embryos and targeted C-to-T conversions were detected in F0 mice.

2020-05-05 | GSE145550 | GEO

Cas12a base editors induce efficient and specific editing with low DNA damage response (RNA sequencing)

2020-05-05 | GSE144278 | GEO

ABE8e adenine base editor precisely and efficiently corrects a COL7A1 nonsense mutation

Project description:Base editing introduces precise single-nucleotide edits in genomic DNA and has the potential to treat genetic diseases such as the blistering skin disease recessive dystrophic epidermolysis bullosa (RDEB), which is characterized by mutations in the COL7A1 gene and type VII collagen (C7) deficiency. Adenine base editors (ABEs) convert A-T base pairs to G-C base pairs without requiring double-stranded DNA breaks or donor DNA templates. Here, we use ABE8e, a recently evolved ABE, to correct primary RDEB fibroblasts harboring the recurrent RDEB nonsense mutation c.5047 C>T (p.Arg1683Ter) in exon 54 of COL7A1 and use a next generation sequencing workflow to interrogate post-treatment outcomes. Electroporation of ABE8e mRNA into a bulk population of RDEB patient fibroblasts resulted in remarkably efficient (94.6%) correction of the pathogenic allele, restoring COL7A1 mRNA and expression of C7 protein in western blots and in 3D skin constructs. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. Taken together, we have established a highly efficient pipeline for gene correction in primary fibroblasts with a favorable safety profile. This work lays a foundation for developing therapies for RDEB patients using ex vivo or in vivo base editing strategies.

2022-08-25 | GSE211876 | GEO

Precise adenine base editors that exhibit minimized cytosine catalysis

Project description:To alleviate the ABE-mediated cytosine editing activity, we engineered the commonly-used version of adenosine deaminase, TadA7.10. We found that the D108Q mutation also reduces cytosine deamination activity in two recently-developed versions of ABE, ABE8e and ABE8s, and has a synergistic effect with V106W, a key mutation that reduces off-target RNA editing.

2021-01-21 | GSE165164 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data