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Adenine Base Editing of Hematopoietic Stem Cells Rescues T-Cell Development for CD3δ Severe Combined Immune Deficiency

ABSTRACT: Adenine Base Editing of Hematopoietic Stem Cells Rescues T-Cell Development for CD3δ Severe Combined Immune Deficiency

PROVIDER: PRJNA910525 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22588219.fastq.gz	Fastqsanger.gz
	SRR22588220.fastq.gz	Fastqsanger.gz
	SRR22588221.fastq.gz	Fastqsanger.gz
	SRR22588222.fastq.gz	Fastqsanger.gz
	SRR22588223.fastq.gz	Fastqsanger.gz

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Adenine Base Editing of Hematopoietic Stem Cells Rescues T-Cell Development for CD3δ Severe Combined Immune Deficiency

Project description:CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPC). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into CD3δ SCID patient’s HSPCs resulted in 71.2±7.85% (n=3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate preclinical efficacy of ABE in HSPC for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.

2023-03-20 | GSE220611 | GEO

Bimodal Adenine and Cytosine CRISPR Base Editing on DNA

Project description:Adenine and cytosine base editors (ABEs and CBEs) represent a new genome editing technology that allows the programmable installation of A-to-G or C-to-T alterations on DNA. We engineered Streptococcus pyogenes Cas9-based adenine and cytosine base editor (SpACE) that enables efficient simultaneous introduction of A-to-G and C-to-T substitutions in the same base editing window on DNA.

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Bimodal Adenine and Cytosine CRISPR Base Editing on DNA

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In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [RNA-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 | GSE168363 | GEO

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

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Targeted exon skipping with AAV-mediated split adenine base editors.

Project description:Techniques for exclusion of exons from mature transcripts have been applied as gene therapies for treating many different diseases. Since exon skipping has been traditionally accomplished using technologies that have a transient effect, it is particularly important to develop new techniques that enable permanent exon skipping. We have recently demonstrated that this can be accomplished using cytidine base editors for permanently disabling the splice acceptor of target exons. We now demonstrate the application of adenine-deaminase base editors to disrupt the conserved adenosine within splice acceptor sites for programmable exon skipping. We also demonstrate that by altering the amino acid sequence of the linker between the adenosine deaminase domain and the Cas9 nickase or by coupling the adenine base editor with a uracil glycosylase inhibitor, the DNA editing efficiency and exon skipping rates improve significantly. Finally, we developed a split base editor architecture compatible with adeno-associated viral packaging. Collectively, these results represent significant progress towards permanent in vivo exon skipping through base editing and, ultimately, a new modality of gene therapy for the treatment of genetic diseases.

2019-09-12 | GSE120125 | GEO

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Base editing mediated correction of severe β0 thalassemia mutations.

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Project description:We used RNA-sequencing data to explore the transcriptome-wide effects of cytosine and adenine deaminases on gene expression induced by base editors.

2021-06-01 | GSE158693 | GEO

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