image: Human Kidney 2 cell showing actin assemblies around endosomes in OCRL1 deficient cells (actin white, endosomes in yellow and pink and nuclei in blue).
Credit: Jonathan Gadsby.
**Joint Press release from Bambino Gesù Children’s Hospital, Rome; Department of Biochemistry and Gurdon Institute, University of Cambridge, UK; Institute of Physiology, University of Zurich, Switzerland; Dent Disease Foundation USA; Lowe Syndrome Association, USA; and Lowe Syndrome Trust, UK**
The Lowe Syndrome Trust UK, Dent Disease Foundation USA and The Lowe Syndrome Association USA have each awarded grants of €20,000 towards a pilot clinical study led Professor Francesco Emma, Head of the Nephrology unit at the Bambino Gesù Children’s hospital in Rome, Italy. The first patients were enrolled into this Phase 2 clinical trial of alpelisib in Dent disease 2 in June.
Dr Emma said, “This is the first trial in patients with Dent disease due to OCRL1 mutations, based on repurposing a drug that targets the underlying mechanism causing the disease. It aims to find out if the drug improves abnormal kidney function”.
Dent disease (type 2) is a rare condition due to inactivating mutations in the OCRL1 gene that affects males. The most common manifestation of the disease is dysfunction of the proximal tubule of the kidney, which manifests as low-molecular-weight (LMW) proteinuria. The disease may be difficult to recognize and can lead to life-threatening complications and kidney failure at a young age. Dent disease can be cured with kidney transplant but there is a shortage of available organs, and a transplant requires lifelong immunosuppression - so a drug treatment would be a significant step forward. Jill Goodrich, Co-Executive Director of the Dent Disease Foundation said, ‘If a treatment is available, we hope that testing for LMW proteinuria will become more widespread to the benefit of not only Dent disease 2 patients but also the other genetic causes of Dent disease. The progress to chronic kidney disease is a burden that affects whole families, and we look forward to hearing about the progress of the research’.
Lowe syndrome is caused by other mutations in the same OCRL1 gene and is a more severe multi-organ condition causing congenital cataracts, intellectual disability, autism-like symptoms and seizures amongst other symptoms. These disorders have a profound effect on patients and their families. Longstanding supporters of the Lowe Syndrome Trust include patrons Jonathan Ross OBE, Penny Lancaster Stewart, and Tony Hadley MBE. Penny Lancaster, Patron of the Lowe Syndrome Trust commented “We are delighted that the Lowe Syndrome Charity is supporting this clinical trial and hopeful that this will be a major breakthrough in the treatment of Dent 2 and Lowe Syndrome and transform the lives of the affected families”.
The trial has been made possible by an international consortium of scientists, clinicians and the patient groups that are funding the study. The drug compound being used - alpelisib - was identified by a collaboration between Dr Jennifer Gallop’s laboratory at the Gurdon Institute and Department of Biochemistry, University of Cambridge UK and Professor Olivier Devuyst’s laboratory at the Institute of Physiology, University of Zurich, Switzerland.
Dr Gallop gave a keynote lecture at the Lowe Syndrome Association conference on 29 June in Cincinnati, Ohio, USA. She talked about the route to treatments and the significance of the trial in Dent 2 patients for their goal of a meaningful treatment by 2030. Rod Ankrom, whose son lives with Lowe syndrome commented, “We have been coming to LSA conferences for 34 years, and for the research at first there were just guesses, and after decades of work, there now really might be a treatment coming down the line”. Jeri Kubicki, President of the Lowe Syndrome Association said, ‘Our boys experience Lowe syndrome in different ways, at different stages. We are exploring multiple avenues and are excited to determine what this clinical trial tells us’.
Dr Gallop and her team at the University of Cambridge have been working on the fundamental science behind the trial for over 15 years. Their research, funded by the Wellcome Trust and Lowe Syndrome Association is on the actin cytoskeleton that is in all cells in our body and important for all functions, like pumping our heart and supporting our immune system. When Gallop worked out that specific lipid molecules in cell membranes are important in controlling the actin cytoskeleton, she saw that there was a link with Lowe syndrome and Dent disease 2, which causes alterations to these lipids. Gallop said: “And excitingly, we realized there’s an existing drug that might be able to help”.
At that time, Dr Gallop reached to the group of Professor Olivier Devuyst (University of Zurich), who has done pioneering work on genetic disorders of the kidney proximal tubule, including the cellular mechanisms and models of Dent disease. Devuyst is co-directing the ITINERARE Research Priority Program in Zurich, which works at translational programs to accelerate drug discovery for rare diseases. Devuyst, Berquez and colleagues were able to test the drug in model kidney cells, and then in a humanized mouse model of Dent disease 2 – that they had just characterized. Working together, the team found that alpelisib did work to rebalance the actin cytoskeleton and improve kidney function in lab models of the diseases. Professor Devuyst commented, ‘This pioneering trial builds on decades of research establishing the crucial role of endolysosomal trafficking in kidney proximal tubule cell function. It also provides a rare opportunity to repurpose a drug that has been decisively useful in another set of rare disorders sharing problems with the small lipids’. These fundamental insights were detailed in a joint publication (Berquez M et al. Kidney Int 2020, with Editorial Commentary), paving the way for the preparation of the Phase 2 clinical trial.
The trial is due to report in October 2026 and if it shows that alpelisib is effective in the Dent disease 2 participants, the hope is that it will also be beneficial to Lowe syndrome patients suffering with kidney disease.
Background information:
About Ospedale Pediatrico Bambino Gesù, Rome, Italy
Bambino Gesù Children’s Hospital, an Institution belonging to the Holy See, is the largest European Paediatric Hospital and Research Center. It cooperates with the main international centres of the sector, acting as a point of reference for children and teenagers coming from all over Italy and from abroad.
Bambino Gesù Children’s Hospital was founded in Rome in 1869 by the Dukes Salviati as the first Italian pediatric hospital, on the model of Paris Hôpital des Enfants Malades. In 1924, it was donated to the Holy See, thus becoming the Pope’s Hospital. In 1985 the Hospital was officially recognized as a Scientific Institute for Research, Hospitalization and Health Care (IRCCS), combining medical care to an intense research activity. In 2006, the Hospital was accredited for the first time by the Joint Commission International (JCI), the organization certifying excellence in safety and quality of care worldwide.
Bambino Gesù Children’s Hospital provides care in all medical and surgical specialties in the paediatric field. Transplantations, genetic and metabolic diseases, medical cardiology and cardiac surgery, neurosciences, onco-haematology and rehabilitation are some of the fields of excellence in treatment and research.
About the Lowe Syndrome Trust, United Kingdom
The Lowe Syndrome Trust is a UK charity (1081241) set up in 2000 by the Thomas family after their son, Oscar, was diagnosed with the condition, and the charity is devoted to supporting families with the condition and to raise funding for medical research. The charity is accredited by the UK National Institute for Health and Care Research.
About the Dent Disease Foundation, United States
The Dent Disease Foundation is a worldwide hub for emerging non-profits that supports awareness amongst clinicians to accelerate the diagnostic journey and research into treatments that will slow progression of kidney disease. Link to donate: https://www.zeffy.com/en-US/donation-form/donate-here-4
About the Lowe Syndrome Association, United States
The Lowe Syndrome Association works globally to support caregivers with information and resources and support life-transforming research. Biennial conferences have been run for 40 years to support families and connect them with world-renowned medical and scientific experts to accelerate progression to meaningful treatments. Link to donate: https://lowesyndrome.org/donate/
About the Institute of Physiology at University of Zurich, Switzerland
The Institute of Physiology at the University of Zurich (UZH) currently hosts about 150 scientists that work in 14 independent research groups. A major focus of research within the Institute is the identification of the mechanisms operating in inherited kidney disorders and causing chronic kidney disease, based on a multidisciplinary approach including human genetics, model organisms and cellular systems. The Institute of Physiology is part of the Swiss National Centre of Competence in Research (NCCR) Kidney Control of Homeostasis (www.nccr-kidney.ch). The institute is recognized for training capacities in cell biology, renal physiology, epithelial disorders, human genetics, and mechanistic studies in mouse and cellular models. The UZH now sits at #1 in Continental Europe and #11 worldwide in the QS World University Rankings under the category “Anatomy and Physiology”.
About the ITINERARE Program at the University of Zurich, Switzerland
The University Research Priority Program (URPP) ITINERARE fosters excellent translational research on rare diseases at the University of Zurich (UZH) and beyond. The URPP ITINERARE aims to develop novel molecular and gene therapies for selected genetic disorders. ITINERARE integrates three major axes on gene therapy, molecular therapies, and ethics, legal and social innovations (ELSI). Currently our consortium includes more than 50 members from 5 UZH faculties, the University Hospital Zurich (USZ) and the University Children’s Hospital Zurich (KISPI). URPP ITINERARE is based on interdisciplinarity and collaborative structures and is the timely answer to the vast unmet medical need and societal challenges of rare diseases. It combines outstanding expertise on specific rare diseases with cutting-edge therapeutic modalities, drug discovery technologies, and specific competences in ELSI innovations. See: https://www.itinerare.uzh.ch/en.html
About the Department of Biochemistry, University of Cambridge, UK
The Department of Biochemistry at the University of Cambridge is a world-leading biochemical research and education facility, building on the University's tradition of scientific enquiry to enable and support outstanding science. As part of the School of the Biological Sciences our excellent undergraduate and postgraduate education programmes develop the next generation of scientists, whilst over 50 research groups led by investigators of international standing collaborate with colleagues around the world to answer fundamental questions on how cells and their constituent molecules work in life and relate to disease.
About the Gurdon Institute, University of Cambridge, UK
Named after its co-founder, Nobel Laureate Sir John Gurdon, the Gurdon Institute (part of the University of Cambridge) is a world-leading centre for research at the interface between developmental and human biology. It is a collaboration between several Departments including the Department of Biochemistry. Work in the Gurdon Institute has made pioneering contributions to the fields of basic cell biology, cellular reprogramming, epigenetics and DNA repair.
Scientists in the Gurdon Institute work on projects ranging from brain development to lung regeneration and have made many pioneering contributions to the fields of basic cell biology, cellular reprogramming, epigenetics and DNA repair. Institute scientists use a range of model systems such as nematode worms, fruit flies, frogs, mammalian cells and organoids to study development and disease at the level of molecules, cells and tissues.
Research conducted at the Institute has so far led to a dozen spin-out companies (including Adrestia, KuDOS Pharmaceuticals, Abcam, Chroma Therapeutics, CellCentric, Mission Therapeutics and STORM Therapeutics) and five candidate drugs. One of these, the PARP inhibitor olaparib (Lynparza), has been approved for use against certain types of ovarian, breast and prostate cancers.
· Previous stories and films:
https://www.eurekalert.org/news-releases/544856
https://www.varsity.co.uk/science/19966
https://www.businessweekly.co.uk/posts/cancer-drug-can-rebalance-kidney-function-in-devastating-genetic-disease
https://www.cambridgenetwork.co.uk/news/cancer-drug-can-rebalance-kidney-function-devastating-genetic-disease
https://www.cam.ac.uk/stories/frog-eggs-and-rare-human-diseases
https://www.youtube.com/watch?v=8cLQ98qFKiQ
https://www.gurdon.cam.ac.uk/public-engagement/lowe-syndrome-me/