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 modality in precision medicine to target gene dysregulation across myriad diseases. Here we present a modular platform to design programmable mRNA therapeutics, Epigenomic Controllers (EC), that control gene expression through directed epigenetic change. By leveraging natural mechanisms, ECs tune expression levels of one or multiple genes with durable effect of weeks-to-months in female mice following a single dose. We design and characterize ECs to multiple target genes and identify an EC that effectively inhibits the cancer- and inflammatory-disorder-associated multi-gene cluster CXCL1-8. With precision targeting of NF-kB signaling and identification of homologous murine surrogates, ECs significantly reduce neutrophil migration in vivo during acute lung inflammation in female mice. A platform approach to EC design for epigenomic modulation expands treatment frontiers for diverse gene targets, including those considered "undruggable."