Lowe syndrome: TIGEM discovery opens the way to the first clinical trial of a new therapeutic strategy

Over two decades of research into the cellular mechanisms underlying Lowe syndrome have led to the identification of a potential therapeutic strategy for this rare genetic disorder, which affects the eyes, nervous system, and kidneys. The findings are described in a study published in Signal Transduction and Targeted Therapy, a Nature Portfolio journal, by the research group led by Antonella De Matteis, Coordinator of the Cell Biology Program at the Telethon Institute of Genetics and Medicine (TIGEM) in Pozzuoli and Full Professor of Cell Biology at the University of Naples Federico II in the Department of Molecular Medicine and Medical Biotechnology. 

The authors described a novel biological mechanism that corrects the main cellular defect responsible for kidney disease in Lowe syndrome and demonstrated the efficacy of piclidenoson (IB-MECA) in restoring kidney cell function across multiple experimental models. The findings stem from the integration of cell biology, drug screening, kidney organoids, and animal models, which enabled the identification and validation of a candidate drug that is now approaching clinical evaluation in humans. 

From Understanding Disease Mechanisms to a Potential Therapy 

Lowe syndrome is caused by mutations in the OCRL gene, which encodes an enzyme involved in the metabolism of phosphoinositides, a family of lipids that regulates membrane identity and the proper trafficking of molecules within the cell. 

For more than two decades, Antonella De Matteis has been investigating the role of this gene and the consequences of its loss of function. When OCRL is defective, a specific phosphoinositide, known as PI(4,5)P₂, accumulates in endosomes, cellular compartments where it is normally present at very low levels. This imbalance disrupts the proper recycling of key cellular receptors, including megalin, which is essential for protein reabsorption in the kidney. 

From Drug Screening to a Novel Biological Mechanism 

To identify potential therapeutic strategies, TIGEM researchers leveraged the institute’s high-content screening platform to analyze more than 1,200 pharmacologically active compounds, including both approved drugs and compounds in advanced stages of clinical development. The screening approach was designed based on a detailed understanding of the cellular defect caused by OCRL loss of function and used the ability of compounds to correct the disease-causing pathological mechanism as the primary selection criterion. 

Among the more than one hundred compounds identified as potentially effective, the most promising candidate was piclidenoson, an adenosine A3 receptor agonist that has already been clinically investigated for other conditions, including psoriasis. The findings were subsequently validated across multiple experimental models, including engineered cell lines, patient-derived renal tubular cells, human kidney organoids generated from pluripotent stem cells, single-cell genomic analyses, and a humanized mouse model of the disease. 

In all of these systems, the researchers demonstrated not only the drug’s ability to improve protein reabsorption by kidney cells, but also the mechanism through which this effect is achieved: by activating the A3 receptor, piclidenoson promotes the consumption of PI(4,5)P₂ through a biological pathway that is independent of the one normally controlled by OCRL. This prevents the pathological accumulation of the lipid within endosomes and restores normal intracellular trafficking.  

The discovery is particularly significant because it points to a strategy that differs from previous approaches based on the relatively non-selective inhibition of enzymes involved in phosphoinositide metabolism. Instead, the study shows that activation of a cell-surface receptor can specifically correct the lipid imbalance that accumulates within endosomes. 

“This is not ‘just’ a case of drug repurposing: we have above all uncovered a novel biological mechanism that could correct a pathological imbalance at the root of the disease. For many years, we have been investigating the role of OCRL and phosphoinositides in the organization of intracellular membranes. We now finally have a tangible opportunity to offer people living with Lowe syndrome and their families, who have supported our work throughout these years, a real prospect for the future.”  says the first author of the study Leopoldo Staiano, researcher at TIGEM and the CNR Institute of Genetic and Biomedical Research (IRGB)

From Scientific Discovery to Clinical Evaluation 

This work provides the scientific foundation for a clinical development program aimed at evaluating piclidenoson in Lowe syndrome. In early August, Can-Fite BioPharma announced the launch of the program based on the results generated by the TIGEM research group and a collaboration agreement with Fondazione Telethon. The clinical study, coordinated by Francesco Emma at the Bambino Gesù Children’s Hospital in Rome, is currently undergoing regulatory review and will assess the drug’s ability to improve renal tubular function in patients. 

In parallel with the scientific research, the group has built a close partnership with the patient community over the years. Antonella De Matteis contributed to the establishment of the Italian Lowe Syndrome Association (AISLO) and has maintained an ongoing dialogue with families, as well as with the Lowe Syndrome Association (USA) and the Lowe Syndrome Trust (UK). This collaboration has facilitated the sharing of biological samples, a deeper understanding of clinical needs, and the development of a network that has been essential for advancing translational research on the disease. 

A New Paradigm for Phosphoinositide Diseases 

According to the authors, the significance of the discovery extends beyond Lowe syndrome itself. The study demonstrates that signals originating at the cell surface can correct pathological alterations in phosphoinositide metabolism within endosomes, restoring the lipid balance required for proper cellular function. 

In humans, dozens of enzymes are involved in phosphoinositide metabolism, and mutations in many of these enzymes are associated with rare genetic disorders. This work therefore proposes a general framework for the development of new therapies targeting diseases caused by defects in phosphoinositide metabolism and intracellular trafficking. 

“The principle identified in this study could also have future applications for the neurological manifestations of Lowe syndrome and, more broadly, for other diseases characterized by defects in intracellular trafficking. This project highlights the value of an integrated approach that combines cell biology, drug screening, organoids, genomics, animal models, and clinical collaborations. The real challenge was not simply to identify a drug, but to build a pathway linking the understanding of a molecular mechanism to a tangible benefit for patients. It is this approach that ultimately made the launch of the clinical trial possible,” concludes Antonella De Matteis.