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

This project has been approved for funding - the activation procedure is still pending

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2023

Congenital Adrenal Hyperplasia (CAH) is a complex genetic disorder characterized by multiple hormonal imbalances. Despite being discovered more than a century ago, no effective treatments are available, especially for its neuropsychiatric and tumor- related complications. There is thus urgent need to better understand their molecular origin. 
To study such complex issues, we leverage our expertise with human organoids, 3D experimental models, that recapitulate key features of human development. Indeed, we previously demonstrated how we can use them to study the molecular effects of hormonal alterations on the human brain.
For this project we will focus on a key regulator of developmental processes called SP5, since we found that it is strongly altered when exposing organoids to androgen and glucocorticoid, the two major hormonal pathways altered in CAH. SP5 is a Tdark, a molecular target for which the structure, function, and interacting drugs are not known. However, we also found several results, previously published by others, that point to SP5 as a key actor for neurodevelopmental and tumorigenic processes. We thus have a strong rationale to better study its molecular function in the context of CAH.
For that we will apply a truly interdisciplinary approach that integrates the most advanced technologies in the fields of stem cell neurobiology and oncology, to identify and prioritize drugs that are already used for different diseases, but that can be repurposed here since, by interacting with SP5, they could revert the molecular problems in CAH patients and prevent adverse complications thus improving quality of life.