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The UB participates in a project to promote research on Menkes disease

Menkes disease, a serious minority hereditary pathology that appears in the neonatal period, is caused by mutations in the ATP7A gene, which encodes a copper transport protein. This disease causes a multisystem disorder of the metabolism of this essential element, which is characterized by progressive neurodegeneration and marked alterations of the connective tissue, in addition to abnormal, frizzy and sparse hair. Linked to the X chromosome, it mainly affects men, while women are usually unaffected carriers. The Menkes International Association has so far registered 45 affected children worldwide.

Boosting research on this serious hereditary minority disease is the aim of the project led by the UAB and the Institute of Neurosciences (INc-UAB), which has the participation of the University of Barcelona (UB), the Pediatric Institute of Rare Diseases (IPER) of Hospital Sant Joan de Déu, the Menkes International Association and The Copper(Less) Committee, which brings together world experts in the disease.

The project involves Ricard Albalat, professor of the Faculty of Biology and member of the Biodiversity Research Institute (IRBio) of the UB, and the experts of the IPER of the Hospital Sant Joan de Déu Francesc Palau - professor in the Department of Surgery and Medico-Surgical Specialties of the Faculty of Medicine and Health Sciences of the UB- and Natalia Serrano, both members of the Sant Joan de Déu Research Institute (IRSJD).

The project is led by Mercè Capdevila, researcher at the Bioorganic and Bioinorganic Synthesis and Applications Research Group of the UAB. As part of the initiative, the UAB and the Menkes International Association (MIa) have signed a donation agreement worth 40,000 euros aimed at establishing the administration and monitoring protocols of a new treatment that could contribute to improving conditions of life for children suffering from the disease and advance studies towards a clinical trial. The UAB experts María Isabel Pividori and Òscar Palacios, professor and associate professor, respectively, of the Department of Chemistry, are also collaborating on the project; Juan Hidalgo, professor in the Department of Cell Biology, Physiology and Immunology and researcher at the INc-UAB, and Javier Carrasco, from the Molecular Biology Service of the INc-UAB.

Searching for more reliable biomarkers of blood copper levels

Although the disease has been known since Menkes described it in 1962, today the treatment is still only symptomatic and does not prevent the progression of the disease. In 2020, however, a study in mice showed that administering copper together with a molecule called elesclomol allowed the Cu-ES complex to reach the interior of brain cells, preventing harmful neurodegenerative changes and making the animals had a normal survival. The drug was therefore presented as a promising strategy for the treatment of the disease.

One of the most difficult challenges in research aimed at clinical application is being able to establish an appropriate dosage for a child of a few months. In addition, copper has a small therapeutic window, so it is necessary that the concentration does not exceed certain safety thresholds and it is essential to be able to follow with reliable measurements day to day the levels of copper in the body. The project started now focuses on studying whether measuring the concentrations of a group of recombinant proteins - called metallothioneins - can provide more reliable guidelines for gradually adapting the dose of Cu-ES to each child.

"We want to determine if metallothioneins can be used as biomarkers of copper levels in Menkes patients, as the scientific literature has pointed out. Until now, these levels have been analyzed with other markers, but they are not very accurate and precise for a task as delicate as the one we intend to undertake", explains Mercè Capdevila, professor in the Department of Chemistry at the UAB and international expert in the field of metallothioneins.

The researchers will conduct the study from enriched fluids and blood and urine samples from children affected by the disease and from the only child in the world who is receiving the drug as a compassionate medicine, with the exceptional authorization of the Agency Española del Medicamento y Productos Sanitarios (AEMPS) since the beginning of this year.

As part of the project, the scientific collaboration of Professor Ricard Albalat, from the Department of Genetics, Microbiology and Statistics of the UB and the IRBio, will focus on producing and purifying metallothioneins to develop a new test that will better determine how the treatment that is being tested affects Menkes patients, so that the doses can be better adjusted.

In turn, the researcher Francesc Palau, assistant professor of pediatrics in the Department of Surgery and Medico-Surgical Specialties of the UB, is the coordinator of the project at the IPER. Its scientific team coordinates the international group Copper (Less) Committee and also addresses the clinical treatment of the child. In addition, the IRSJD Pharmacy Service - with the experts Miquel Villaronga and Rosa Farré - prepares the formulation of the medicine. Within the framework of the IPER, they also carry out basic research studies (Janet Hoenikka) and coordinate with the Neurology Service (Àngels Garcia Cazorla).
Before the end of 2023, the researchers hope to successfully complete this first stage. "Our studies must also allow progress towards the efficiency, biosafety and toxicity tests of Cu-ES which are required to apply for a clinical trial", concludes Mercè Capdevila.

The donation from the Menkes International Association, which will enable the recruitment of a postdoctoral researcher, has been made possible thanks to the support of the Belgian Foundation of Menkes Voor William, created in memory of a sick child who, unfortunately, died in the summer past His family has decided to promote scientific research in order to advance the cure of this minority disease and thus help other families.

More info: https://www.uab.cat/web/newsroom/news-detail/the-uab-receives-a-donation-of-40-000-euros-to-advance-in-the-study-of-menkes-disease-1345830290613.html?detid=1345875210449