Omega Therapeutics, Inc. announced the presentation of new preclinical data from two different programs that demonstrated sustained upregulation of gene expression and coordinated pre-transcriptional downregulation of multiple genes in models of liver fibrosis and inflammation, respectively, at the American Association for the Study of Liver Diseases' (AASLD) The Liver Meeting 2023, taking place in Boston, Massachusetts, November 10 - 14. Poster 3444-A: Induction of Hepatocyte Nuclear Factor 4 alpha (HNF4a) using novel epigenomic controllers. Key Findings: Human cell lines treated with an epigenomic controller (EC) engineered to modulate the epigenetic profile of the P1 promoter of the HFN4a gene, a master regulator of liver development and function, showed strong increases of mRNA and protein levels.

Upregulation of HFN4a expression following a single EC treatment persisted for =10 days and induced strong and durable increases in HNF4a mRNA levels in primary human hepatocytes. EC-mediated upregulation of HNF4a expression correlated with significantly reduced expression of clinically relevant fibrotic genes in vitro. Single administration of an EC in the humanized FRG mouse model resulted in induction of HNF4a mRNA levels compared to untreated FRG mice.

EC-mediated induction of HNF4a expression in vivo in a mouse model of liver fibrosis led to decreased collagen deposition, a key marker of fibrosis. Regulation of HNF4a also led to changes in expression of other fibrosis-associated genes. Poster 2621-A: Targeting CXCL9/CXCL10/CXCL11 using novel epigenomic controllers for the treatment of inflammatory liver disease.

Key Findings: Treatment of mouse and human liver cells with ECs engineered to pre-transcriptionally downregulate the expression CXCL9, CXCL10 and CXCL11 resulted in robust mRNA downregulation and decreased protein levels of all three chemokines. Primary human hepatocytes stimulated with interferon gamma (INFG) and treated with a single EC targeting CXCL9-11 resulted in a statistically significant decrease in mRNA expression and protein levels of each chemokine compared to INFG stimulation alone. Human T cells exposed to conditioned media from primary human hepatocytes treated with INFG and an EC targeting CXCL9-11 displayed 75% reduced migration compared to cells treated with INFG alone.