An actionable GPCR restores phosphoinositide homeostasis and kidney function in Lowe syndrome

Abstract Oculo-Cerebro-Renal-Lowe syndrome, caused by loss of the PI(4,5)P₂ 5-phosphatase OCRL, is a rare and severe disorder that lacks curative therapy. By integrating deep cell-biological insight into endosomal trafficking and proximal tubule protein reabsorption with high-content screening across engineered cell lines, patient-derived proximal tubule cells, human kidney organoids, and a humanized mouse model, we identify IB-MECA, an oral adenosine A3 receptor agonist, as a targeted therapy poised for clinical evaluation. IB-MECA normalizes endosomal PI(4,5)P₂ homeostasis, restores receptor trafficking, and rescues protein reabsorption in all systems, demonstrating the translational power of a mechanism-anchored, cross-species screening pipeline that couples cellular correction to organ-level benefit and supports rapid progression toward phase II testing pending regulatory approval. Mechanistic dissection revealed that IB-MECA acts through A3AR-dependent activation of PLC, revealing a previously unrecognized axis whereby receptor-driven hydrolysis of plasma-membrane PI(4,5)P₂ corrects pathological endosomal PI(4,5)P₂ accumulation. This receptor-mediated rewiring of phosphoinositide homeostasis contrasts with earlier strategies based on broad kinase inhibition and establishes plasma-membrane GPCR–PLC signaling as a precise, druggable entry point to correct endolysosomal lipid imbalance. Together with the favorable clinical safety record of IB-MECA, these findings provide a compelling rationale for an imminent clinical trial (NCT07410455) in Lowe syndrome and outline a generalizable, cell biology–guided framework for developing therapies for inherited disorders of phosphoinositide metabolism.