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MRNA-Engineered CRISPR-Cas Epigenetic Editors Enable Durable and Efficient Gene Silencing in Vivo [WGBS]

ABSTRACT: mRNA-Engineered CRISPR-Cas Epigenetic Editors Enable Durable and Efficient Gene Silencing in Vivo [WGBS]

PROVIDER: PRJNA1273163 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33871719_1.fastq.gz	Fastqsanger.gz
	SRR33871719_2.fastq.gz	Fastqsanger.gz
	SRR33871720_1.fastq.gz	Fastqsanger.gz
	SRR33871720_2.fastq.gz	Fastqsanger.gz
	SRR33871721_1.fastq.gz	Fastqsanger.gz

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mRNA-Engineered CRISPR-Cas Epigenetic Editors Enable Durable and Efficient Gene Silencing in Vivo [WGBS]

Project description:Programmable epigenetic editors that achieve long-term gene expression modulation hold immense therapeutic potential. However, the large size of current CRISPR-based epigenome editors has limited their widespread application. This study describes the engineering of compact, mRNA-delivered epigenetic repressors, termed CRISPR OFF-EE, using SpyCas9, intein-based split-SpyCas9 or the smaller SF01 Cas variant, to achieve highly efficient and durable silencing of endogenous genes. We developed "superfolder" V2 mRNA constructs with optimized codon usage, UTRs, and nuclear localization signals, which enhanced mRNA stability, translational output, and LNP packaging. These CRISPR OFF-EE V2 editors demonstrated significantly improved and durable gene silencing across multiple targets in variable cell lines. Remarkably, a single intravenous administration of lipid nanoparticles (LNPs) encapsulating the optimized OFF-EE-V2 mRNA and selected sgRNAs targeting PCSK9 in mice led to an approximately 90% reduction in circulating PCSK9 protein and a 55% reduction in LDL-C levels, with effects persisting for at least 180 days. Whole-genome bisulfite sequencing confirmed the high specificity of these editors, with SF01-based editors exhibiting fewer off-target methylation events than SpCas9-based editors. The platform also demonstrated multiplexing capability and a favorable safety profile with liver-restricted activity. These findings establish a robust foundation for advancing in vivo therapeutics based on precise and durable epigenetic silencing using transiently delivered mRNA editors.

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mRNA-Engineered CRISPR-Cas Epigenetic Editors Enable Durable and Efficient Gene Silencing in Vivo [RNA-seq]

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mRNA-Engineered CRISPR-Cas Epigenetic Editors Enable Durable and Efficient Gene Silencing in Vivo [RNA-seq]

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mRNA-Engineered CRISPR-Cas Epigenetic Editors Enable Durable and Efficient Gene Silencing in Vivo

Project description:This SuperSeries is composed of the SubSeries listed below.

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Replacing the SpCas9 HNH domain by deaminases generates compact base editors with an alternative targeting scope

Project description:Base editors are RNA-guided deaminases that enable site-specific nucleotide transitions. The targeting scope of these Cas-deaminase fusion proteins critically depends on the availability of a protospacer adjacent motif (PAM) at the selected genomic locus, and is limited to a window within the CRISPR-Cas R-loop where single stranded (ss)DNA is accessible to the deaminase. Here, we reason that the Cas9-HNH nuclease domain sterically constrains ssDNA accessibility, and demonstrate that omission of this domain expands the editing window. By exchanging the HNH nuclease domain with an adenosine deaminase, we furthermore engineer adenine base editor variants (HNHx-ABE) with PAM-proximally shifted editing windows. HNHx-ABEs are substantially reduced in size, and expand the targeting scope of base editors. Our finding that the HNH domain is replaceable could moreover benefit future protein engineering efforts, where Cas9 operates together with other enzyme domains.

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Replacing the SpCas9 HNH domain by deaminases generates compact base editors with an alternative targeting scope [RNA-seq]

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