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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [AmpliconSeq]

ABSTRACT: Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [AmpliconSeq]

PROVIDER: PRJNA1046097 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26973256_1.fastq.gz	Fastqsanger.gz
	SRR26973256_2.fastq.gz	Fastqsanger.gz
	SRR26973257_1.fastq.gz	Fastqsanger.gz
	SRR26973257_2.fastq.gz	Fastqsanger.gz
	SRR26973258_1.fastq.gz	Fastqsanger.gz

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair

Project description:Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [Amplicon]

Project description:Homology Directed Repair (HDR) enables precise genome editing and holds great promise in the gene therapy field. However, the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we demonstrate the development of a functional, pooled screening platform utilizing an HDR-based readout to identify protein-based reagents that improve HDR outcomes in human hematopoietic stem and progenitor cells (HSPCs), a clinically relevant cell type for gene therapy. We leveraged this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, and we identified optimized i53 variants that enable new intermolecular bonds and robustly increase HDR. These variants specifically reduce insertion-deletion outcomes and also synergize with a DNAPK inhibitor to increase HDR rates. When applied at manufacturing scale, the incorporation of improved variants results in a significant increase in cells with at least one repaired allele and improved HDR in long-term HSPCs subpopulations, while not increasing off-target editing or gross chromosomal rearrangements. We anticipate the pooled screening platform will enable discovery of future gene editing reagents that improve HDR outcomes, such as the i53 variants reported here.

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [i53]

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [AmpliconSeq]

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [i53]

Project description:Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [i53]

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [Amplicon]

Project description:Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [Amplicon]

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [scRNA-Seq]

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [scRNA-Seq]

Project description:Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair [scRNA-Seq]

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Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair.

Project description:Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we develop a functional, pooled screening platform to identify protein-based reagents that improve HDR in human hematopoietic stem and progenitor cells (HSPCs). We leverage this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, identifying optimized variants that enable new intermolecular bonds and robustly increase HDR. We show that these variants specifically reduce insertion-deletion outcomes without increasing off-target editing, synergize with a DNAPK inhibitor molecule, and can be applied at manufacturing scale to increase the fraction of cells bearing repaired alleles. This screening platform can enable the discovery of future gene editing reagents that improve HDR outcomes.

| S-EPMC10960832 | biostudies-literature

Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair

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

2024-02-11 | GSE242757 | GEO