DT-VEXAS

VEXAS syndrome is a newly discovered, adult-onset, incurable hemato-inflammatory disease caused by somatic mutations of the UBA1 gene in hematopoietic stem/progenitor cells (HSPC) (Beck et al, 2020). We found that pervasive inflammation in the bone marrow (BM) poisons healthy hematopoiesis sparing UBA1 mutant cells (Molteni et al, under invited review). The resulting unprecedented interplay of inflammation and clonal dominance dictates progressive BM failure. To decipher and target such interplay, exploiting our unique UBA1-edited HSPCs (patent PCTIB2024060412) and our clinical VEXAS patient cohort, we will: i) dissect cell-autonomous and intercellular pathomechanisms by multi-omics phenotyping along and across hematopoiesis and molecular/functional assays in vitro; ii) validate them by characterizing BM and peripheral hematopoietic cells from VEXAS patients; iii) identify targets for mutant cell-specific drug delivery of established or repurposed compounds against pathogenic clones.