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The Gurdon Institute

09.09.20 Drug developed for cancer, alpelisib, restores kidney function in Lowe syndrome and Dent disease

The Gallop Lab show that alpelisib alleviates actin defects, endocytic blockage and restores kidney function in the mouse model of Lowe syndrome and Dent disease 2, in a collaboration with the Devuyst lab at the University of Zurich

The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease

Berquez M et al. (2020) Kidney International 

98 (4): 883-896.

DOI: 10.1016/j.kint.2020.05.040.


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Abstract from the paper 

Loss-of-function mutations in the OCRL gene, which encodes the phosphatidylinositol [PI] 4,5-bisphosphate [PI(4,5)P2] 5-phosphatase OCRL, cause defective endocytosis and proximal tubule dysfunction in Lowe syndrome and Dent disease 2. The defect is due to increased levels of PI(4,5)P2 and aberrant actin polymerization, blocking endosomal trafficking. PI 3-phosphate [PI(3)P] has been recently identified as a coactivator with PI(4,5)P2 in the actin pathway.

Here, we tested the hypothesis that phosphoinositide 3-kinase (PI3K) inhibitors may rescue the endocytic defect imparted by OCRL loss, by  rebalancing phosphoinositide signals to the actin machinery. The broad-range PI3K inhibitor copanlisib and class IA p110 alpha PI3K inhibitor alpelisib reduced aberrant actin polymerization in OCRL-deficient human kidney cells. Levels of PI 3,4,5-trisphosphate, PI(4,5)P2 and PI(3)P were all reduced with alpelisib treatment, and siRNA knockdown of the PI3K catalytic subunit p110 alpha phenocopied the actin phenotype. In a humanized OcrlY/- mouse model, alpelisib reduced endosomal actin staining while restoring stress fiber architecture and levels of megalin at the plasma membrane of proximal tubule cells, reflected by improved endocytic uptake of low molecular weight proteins in vivo.

Our findings support the link between phosphoinositide lipids, actin polymerization and endocytic trafficking in the proximal tubule, and represent a proof-of-concept for repurposing alpelisib in Lowe syndrome/Dent disease 2.

GallopBerquez abstract



Read more about the Gallop lab.

Olivier Devuyst lab at the University of Zurich.

Watch Jenny Gallop describe her lab's research on You Tube.

Read Business Weekly's write-up of this research.

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