{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Telethon Institute of Genetics and Medicine, Naples, Italy",
    "Institute for Genetic and Biomedical Research, National Research Council (IRGB-CNR), Milan, Italy",
    "Glaxo Smith Kline, Stevenage, UK",
    "Scuola Superiore Meridionale (School of Advanced Studies), Genomics and Experimental Medicine Program (GEM), Naples, Italy",
    "Department of Molecular Medicine and Medical Biotechnology (DMMBM), University of Naples “Federico II”, Naples, Italy",
    "Institute for Applied Mathematics “Mauro Picone”, National Research Council of Italy, Naples, Italy",
    "Department of Translational Medical Sciences (DISMET), University of Naples “Federico II”, Naples, Italy",
    "Biogem, Molecular Biology and Genetics Research Institute, Ariano Irpino, Italy",
    "Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, Naples, Italy",
    "Division of Nephrology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy",
    "Institut de Recherche Experimentale et Clinique, UCLouvain, Brussels, Belgium",
    "Department of Physiology, University of Zurich, Zurich, Switzerland",
    "Labcorp (Formerly Invitae Corp), San Francisco, CA USA"
  ],
  "article_type": "research article",
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  "author_total": 20,
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        0,
        1
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      "name": "Leopoldo Staiano",
      "orcid": "0000-0001-7017-1516"
    },
    {
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        0
      ],
      "name": "Marialuisa Testa",
      "orcid": "0009-0004-4269-1951"
    },
    {
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        2
      ],
      "name": "Mariella Vicinanza"
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    {
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        3
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      "name": "Francesca Cervellini"
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      "name": "Laura Giaquinto"
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      "name": "Lorenzo Patanella"
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    {
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        0
      ],
      "name": "Giuseppe Di Tullio"
    },
    {
      "affs": [
        0
      ],
      "name": "Michele Santoro"
    },
    {
      "affs": [
        5
      ],
      "name": "Annamaria Carissimo"
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    {
      "affs": [
        0
      ],
      "name": "Alessandro Giordano"
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    {
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        0
      ],
      "name": "Michele Genovese"
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        6
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      "name": "Luis Juan Vicente Galietta"
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      "name": "Anna Iervolino"
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    {
      "affs": [
        7
      ],
      "name": "Antonio Miele"
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    {
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        6
      ],
      "name": "Diego Luis Medina"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Francesco Trepiccione"
    },
    {
      "affs": [
        9
      ],
      "name": "Francesco Emma"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Olivier Devuyst"
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    {
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        12
      ],
      "name": "Robert Nussbaum"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Maria Antonietta De Matteis",
      "orcid": "0000-0003-0053-3061"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6kr09tbs8d0d8.bib",
  "cited_by": 0,
  "doi": "10.1038/s41392-026-03054-z",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13731648/",
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  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
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  "pdf_url": "https://www.nature.com/articles/s41392-026-03054-z.pdf",
  "pmcid": "PMC13731648",
  "pmid": "42977741",
  "published": "2026-11-04",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/6kr09tbs8d0d8.ris",
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  "subjects": [
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      "origin": "openalex:1307|Cellular transport and secretion",
      "subfield": "cell-biology"
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  "title": "An actionable GPCR restores phosphoinositide homeostasis and kidney function in Lowe syndrome",
  "title_text": "An actionable GPCR restores phosphoinositide homeostasis and kidney function in Lowe syndrome",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:21:48Z",
  "url": "https://research.draconitic.com/paper/6kr09tbs8d0d8",
  "venue": "Signal Transduction and Targeted Therapy",
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