A pharmacological strategy to correct a deficiency in a renal transcription factor – RENBOOST

Congenital and adult-onset disorders affecting kidney development and tubular homeostasis are frequently caused by mutations in genes that regulate epithelial differentiation. Among these, one transcriptional regulator plays a central role in kidney morphogenesis and in maintaining tubular integrity and function. When one copy of this gene is inactive, individuals may present developmental anomalies of the urinary tract or progressive tubulointerstitial disease in adulthood. Despite the clinical importance of these conditions, the underlying molecular mechanisms remain insufficiently understood, and no targeted therapeutic strategy is currently available beyond renal replacement therapies.

Recent findings suggest that reduced dosage of this transcription factor leads to insufficient transcriptional activity (haploinsufficiency). Because its activity appears constitutive yet relatively weak, enhancing its functional output through pharmacological means could represent a promising therapeutic avenue. To explore this possibility, we developed a cell-based biosensor capable of monitoring the transcriptional output of this factor in renal epithelial cells.

Using this system, we performed a high-throughput screen of an approved-drug library and identified several compounds capable of increasing the activity of the biosensor.

The objective of this project is to evaluate the therapeutic potential of these compounds in models of reduced gene dosage, both in patient-derived renal epithelial cells and in an established preclinical model displaying haploinsufficiency during development and postnatal life. In parallel, we will investigate the molecular mechanisms through which these drugs enhance transcriptional output.

If successful, this project will establish a novel repositioning-based therapeutic strategy for a severe inherited kidney disorder. Because the identified compounds are already approved for human use, positive preclinical results could rapidly pave the way for clinical evaluation.