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Incorporating programmable DNA-binding domains enhances the efficiency and flexibility of miniature CRISPR base editors

ABSTRACT: Incorporating programmable DNA-binding domains enhances the efficiency and flexibility of miniature CRISPR base editors

PROVIDER: PRJNA1250402 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33133518_1.fastq.gz	Fastqsanger.gz
	SRR33133518_2.fastq.gz	Fastqsanger.gz
	SRR33133519_1.fastq.gz	Fastqsanger.gz
	SRR33133519_2.fastq.gz	Fastqsanger.gz
	SRR33133520_1.fastq.gz	Fastqsanger.gz

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Incorporating programmable DNA-binding domains enhances the efficiency and flexibility of miniature CRISPR base editors

Project description:The therapeutic application of base editors is currently limited by their large sizes, which are often beyond the packaging capabilities of adeno-associated viral (AAV) vectors. Despite recent progress in mega genome mining that has identified a diverse array of compact CRISPR proteins (e.g. Cas12f, TnpB, and IscB), the resulting miniature base editors are often exhibited reduced activities and a limited targeting scope, leaving a broad spectrum of disease-relevant genetic variants inaccessible. In this study, we have developed a platform, designated as Zinc Finger Proteins (ZFP)-enhanced miniature base editor (zmBE), which integrates programmable DNA-binding domains to enhance the efficiency and expand targeting scope of miniature base editors, including those based on Un1Cas12f1 and OgeuIscB. Utilizing protein language model (PLM) for the design of ZFPs further simplified development and optimization of zmBEs tailored to a specific target. Leveraging these methodologies, we engineered a zmBE that effectively induced the SMN2 exon 7 A6>G conversion and restored SMN2 exon 7 inclusion. Our study thus provides a versatile platform for developing miniature base editors for in vivo therapeutic applications.

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CRISPR-SKIP: Programmable Gene Splicing with Single Base Editors

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CRISPR-SKIP: Programmable Gene Splicing with Single Base Editors [RNA-seq]

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CRISPR-SKIP: Programmable Gene Splicing with Single Base Editors [off-targets]

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CRISPR-SKIP: Programmable Gene Splicing with Single Base Editors [gDNA]

Project description:CRISPR gene editing has revolutionized biomedicine and biotechnology by providing a simple means to engineer genes in vivo by introducing mutations at target sites in the genomic DNA of living cells. However, given the stochasticity of cellular DNA repair mechanisms and the potential for introducing mutations at off-target sites, technologies capable of introducing targeted changes with increased precision, such as cytidine deaminase single-base editors, are preferred. We here present a versatile method termed CRISPR-SKIP that utilizes cytidine deaminase single-base editors to program de-novo exon skipping by mutating target DNA bases within splice acceptor sites. Given its simplicity and precision, CRISPR-SKIP will be broadly applicable in gene therapy and synthetic biology.

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CRISPR-SKIP: Programmable Gene Splicing with Single Base Editors [RNA-seq]

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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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