An actionable GPCR restores phosphoinositide homeostasis and kidney function in Lowe syndrome
13 affiliations
- 1Telethon Institute of Genetics and Medicine, Naples, Italy
- 2Institute for Genetic and Biomedical Research, National Research Council (IRGB-CNR), Milan, Italy
- 3Glaxo Smith Kline, Stevenage, UK
- 4Scuola Superiore Meridionale (School of Advanced Studies), Genomics and Experimental Medicine Program (GEM), Naples, Italy
- 5Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples “Federico II”, Naples, Italy
- 6Institute for Applied Mathematics “Mauro Picone”, National Research Council of Italy, Naples, Italy
- 7Department of Translational Medical Sciences (DISMET), University of Naples “Federico II”, Naples, Italy
- 8Biogem, Molecular Biology and Genetics Research Institute, Ariano Irpino, Italy
- 9Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, Naples, Italy
- 10Division of Nephrology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy
- 11Institut de Recherche Experimentale et Clinique, UCLouvain, Brussels, Belgium
- 12Department of Physiology, University of Zurich, Zurich, Switzerland
- 13Labcorp (Formerly Invitae Corp), San Francisco, CA USA
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.
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BibTeX
@article{staiano2026actionable,
title = {{An actionable GPCR restores phosphoinositide homeostasis and kidney function in Lowe syndrome}},
author = {Leopoldo Staiano and Marialuisa Testa and Mariella Vicinanza and Francesca Cervellini and Laura Giaquinto and Lorenzo Patanella and Giuseppe Di Tullio and Michele Santoro and Annamaria Carissimo and Alessandro Giordano and Michele Genovese and Luis Juan Vicente Galietta and Anna Iervolino and Antonio Miele and Diego Luis Medina and Francesco Trepiccione and Francesco Emma and Olivier Devuyst and Robert Nussbaum and Maria Antonietta De Matteis},
journal = {Signal Transduction and Targeted Therapy},
year = {2026},
month = nov,
doi = {10.1038/s41392-026-03054-z},
url = {https://doi.org/10.1038/s41392-026-03054-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - An actionable GPCR restores phosphoinositide homeostasis and kidney function in Lowe syndrome
AU - Leopoldo Staiano
AU - Marialuisa Testa
AU - Mariella Vicinanza
AU - Francesca Cervellini
AU - Laura Giaquinto
AU - Lorenzo Patanella
AU - Giuseppe Di Tullio
AU - Michele Santoro
AU - Annamaria Carissimo
AU - Alessandro Giordano
AU - Michele Genovese
AU - Luis Juan Vicente Galietta
AU - Anna Iervolino
AU - Antonio Miele
AU - Diego Luis Medina
AU - Francesco Trepiccione
AU - Francesco Emma
AU - Olivier Devuyst
AU - Robert Nussbaum
AU - Maria Antonietta De Matteis
PY - 2026
DA - 2026/11/04
JO - Signal Transduction and Targeted Therapy
DO - 10.1038/s41392-026-03054-z
UR - https://doi.org/10.1038/s41392-026-03054-z
AB - 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.
SN - 2095-9907
SN - 2059-3635
ER -