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Cancer drug can rebalance kidney function in a devastating genetic disease

September 09, 2020

Researchers at the University of Cambridge and the University of Zurich have discovered that a drug newly approved for cancer improves kidney dysfunction in a mouse model of Dent disease 2 and Lowe syndrome

The study is published today in Kidney International and offers hope for the first disease-modifying treatment. In addition to kidney dysfunction, characteristic of Dent disease 2, boys with Lowe syndrome also require eye cataract surgery as newborns, and suffer seizures and other disabilities. Only supportive treatments are available, such as nutrient supplements and help with learning.

These rare diseases are caused by the lack of an enzyme called OCRL that normally controls the lipid composition of cell membranes. The disruption activates a system of filaments inside the cells, called the actin cytoskeleton, in the wrong place. The actin blockage means that the cells in the kidneys that usually reabsorb filtered proteins and essential nutrients don't work properly, causing a loss of these in the urine.

Dr Jennifer Gallop's group at the Wellcome Trust/ Cancer Research UK Gurdon Institute in Cambridge worked out how the actin system was being activated by the disruption in cell membrane lipids. "By understanding the details of what is happening in cells during Lowe syndrome and Dent disease 2," said Dr Gallop, "we realised that alpelisib, a drug that is already approved for use in patients with cancer, could prevent the actin blockage". This is because alpelisib targets a different step in the pathway, and rebalances the lipid composition.

The Gallop group teamed up with Professor Oliver Devuyst from the Institute of Physiology, University of Zurich to test alpelisib in a humanized mouse model of Lowe syndrome and Dent disease 2. Devuyst said "amazingly, treatment with alpelisib improved the actin cytoskeleton of the kidney cells and rescued the reabsorption of the filtered proteins".

The researchers don't yet know whether the drug will work in patients and if their neurological symptoms will be helped as well. However, because alpelisib has been used before in another rare disease in children, as well as in adults, there is evidence that it is safe. These efforts of repurposing a drug could potentially lead to the cost-effective development of a treatment for these rare disorders.

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 (

About the Wellcome Trust/ Cancer Research UK Gurdon Institute at the 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 biology and cancer biology.

More than 200 scientists work in the Gurdon Institute's purpose-built laboratories on projects ranging from breast cancer and brain development to lung regeneration and mitochondrial disease. Many have made 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 yeast, 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 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.

Wellcome Trust/ Cancer Research UK Gurdon Institute

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