SP5 as novel mediator of CAH multi-organ pathogenesis: from functional elucidation to therapeutic repurposing

Congenital Adrenal Hyperplasia (CAH) is a genetic disorder caused by deficiency of the enzyme that synthesize cortisol in the adrenal cortex. This has cascading effects, leading to multiple hormonal imbalances. Despite CAH was first described more than 150 years ago, patients still suffer disease- and treatment-related adverse outcomes. In particular, CAH patients are heavily affected by neuropsychiatric morbidity, and by Testicular Adrenal Rest Tumors, two serious complications that are still poorly understood. In this project we aim to elucidate their molecular pathogenesis, experimentally manipulating hormonal signaling pathways in a unique set of human organoids models. Building on our previous work we found the key observation that the transcription factor SP5 was significantly altered by hormonal exposure on human organoids. SP5 coordinates transcription in the developing embryo, being a prototypical target of the WNT/β-catenin pathway, and several genome wide association studies associated it to cognitive traits. This combination of evidences represents a strong rationale to hypothesize that SP5 is a key molecular player for the neuropsychiatric and tumorigenic events in CAH. Leveraging pluripotent stem cells and organoids, genome engineering, single cell transcriptomics, and imaging we will: (i) study the impact of the exposure to androgen and glucocorticoid during organoids differentiation; (ii) engineer an inducible system to modulate the expression of SP5 and test its ability to revert the molecular and cellular phenotypes induced by hormonal exposure; (iii) prioritize drugs, through repurposing strategies, that interact with SP5 and its targets, for pre-clinical validation. Bridging the knowledge gap in the pathogenesis of CAH complications, we will propose new therapeutic and preventive approaches for improving patients’ quality of life, and contribute to advancing our basic knowledge on the role of hormonal axes on brain and tumor development.