Sustained and specific multiplexed immune checkpoint modulation in CAR T cells induced by targeted epigenome editing.

Engineered T cells equipped with a chimeric antigen receptor (CAR) have shown tremendous clinical success, but tumor-mediated stimulation of T cell inhibitory receptors leads to exhaustion, hampering durable remission in patients. Mitigation of this effect via checkpoint inhibition or genome editing to knockout the genes encoding for these receptors has shown promise. Yet, the side effects of these procedures require better alternatives.

A versatile reporter system for multiplexed screening of effective epigenome editors.

The formation and function of highly specialized cells and tissues in a multicellular organism from a single genome are enabled through differential spatiotemporal access to the information contained in the genomic DNA. The epigenome plays an essential role in how DNA information can be accessed, and in the last decade the link between epigenetic aberrations and pathologies has become increasingly clear. Methods to precisely modify the epigenome are hence attracting interest as potential novel therapeutics.

SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation.

Sirtuin 3 (SIRT3) is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress. Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances. In this study, we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells.