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Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis [RNA-seq_PBMC]

ABSTRACT: Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis [RNA-seq_PBMC]

PROVIDER: PRJNA957897 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24234848.fastq.gz	Fastqsanger.gz
	SRR24234849.fastq.gz	Fastqsanger.gz
	SRR24234850.fastq.gz	Fastqsanger.gz
	SRR24234851.fastq.gz	Fastqsanger.gz
	SRR24234852.fastq.gz	Fastqsanger.gz

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Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis

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Project description:The development of new immunotherapies to treat the inflammatory mechanisms that sustain atherosclerotic cardiovascular disease (ASCVD) is urgently needed. Herein, we present a path to drug repurposing to identify immunotherapies for ASCVD. The integration of time-of-flight mass cytometry and RNA sequencing identified unique inflammatory signatures in peripheral blood mononuclear cells stimulated with ASCVD plasma. By comparing these inflammatory signatures to large-scale gene expression data from the LINCS L1000 dataset, we identified drugs that could reverse this inflammatory response. Ex vivo screens, using human samples, showed that saracatinib-a phase 2a-ready SRC and ABL inhibitor-reversed the inflammatory responses induced by ASCVD plasma. In Apoe-/- mice, saracatinib reduced atherosclerosis progression by reprogramming reparative macrophages. In a rabbit model of advanced atherosclerosis, saracatinib reduced plaque inflammation measured by [18F] fluorodeoxyglucose positron emission tomography-magnetic resonance imaging. Here we show a systems immunology-driven drug repurposing with a preclinical validation strategy to aid the development of cardiovascular immunotherapies.

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