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Programmable mRNA Therapeutics for Controlled Epigenomic Modulation of Single and Multiplexed Gene Expression in Diverse Diseases (human data)

ABSTRACT: Pathogenic gene dysregulation can be attributed to chromatin state change that pre-transcriptionally regulates expression. Recent breakthroughs elucidating the rules governing this DNA control layer, an epigenetic code, unlock a new modality in precision medicine to target gene dysregulation across myriad diseases. Leveraging these natural mechanisms, we developed a modular platform to design programmable mRNA therapeutics, Epigenomic Controllers (EC), that control gene expression through directed epigenetic change. ECs tune expression levels of one or multiple genes with durable effect of weeks-to-months in vivo following a single dose. We characterized ECs across multiple targets and designed an EC effectively inhibiting the cancer- and inflammatory-disorder-associated multi-gene cluster CXCL1-8. With precision targeting of NF-kB signaling and novel identification of homologous murine surrogates, ECs significantly reduced neutrophil migration in vivo during acute lung inflammation. A platform approach to EC design for epigenomic modulation opens new treatment frontiers for diverse gene targets, including those considered "undruggable."

ORGANISM(S): Homo sapiens

PROVIDER: GSE290866 | GEO | 2025/03/04

REPOSITORIES: GEO

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