The Renal Pathophysiology Group at the Vall d’Hebron Research Institute (VHIR) has launched a new research project, led by Dr. Cristina Martínez as principal investigator and in partnership with the Association for Information and Research on Familial Hypomagnesemia (Hipofam), to establish new laboratory models to study familial hypomagnesemia with hypercalciuria and nephrocalcinosis (HFHNC), a rare disease that primarily affects the kidneys. The study, funded by the Spanish Federation of Rare Diseases (FEDER), is being carried out in collaboration with the Pediatric Nephrology Service of Vall d’Hebron University Hospital, led by Dr. Gema Ariceta, and the Tissue Engineering Unit led by Dr. Laura Batlle at the Centre for Genomic Regulation (CRG). This project continues the line of research initiated and led by Dr. Anna Meseguer over the past ten years, until her recent retirement.

FHHNC is a very rare kidney disease caused by mutations in the claudin 19 gene (CLDN19), the most common mutation in our setting, or in claudin 16 (CLDN16), both of which are involved in normal kidney function. Despite the key role of these mutations, other genetic variants have been identified recently by the same team that influence whether renal deterioration progresses more quickly or more slowly in each patient. This explains why two individuals with the same CLDN19 mutation may have very different clinical courses.

“It is essential to develop advanced models that allow us to study the pathophysiology of the disease in depth, understand the role of these risk variants, identify predictive biomarkers and assess therapeutic strategies”, explains Dr Gema Ariceta, head of the Paediatric Nephrology Department at Vall d’Hebron University Hospital and of the Kidney Pathophysiology group at VHIR.

“Mini-kidneys” in the laboratory to study the disease

In order to obtain new disease models, the VHIR team has obtained cells from two sibling patients who share the same CLDN19 mutation but show very different clinical progression. Despite having the same mutation, it has been confirmed that the patient with faster progression carries genetic variants associated with more severe kidney deterioration.

From samples obtained from these two patients, two induced pluripotent stem cell lines have already been established, homozygous for the p.G20D mutation in CLDN19. Using CRISPR gene editing, two isogenic lines with the corrected mutation will be generated. This will make it possible to directly compare the effect of the p.G20D mutation against the patients’ genetic background and to isolate the impact of risk variants on disease progression.

Based on these lines, the project will develop 3D renal organoids, which behave like small kidneys and allow the molecular and functional features of the disease to be reproduced more faithfully than conventional 2D cell cultures.

“Organoids will allow us to study functionality according to mutations and variants, their impact on kidney development, and they will also provide a key platform for testing new drugs”, highlights Dr Cristina Martínez.

These tools may also be useful for studying other rare diseases with similar clinical features and for advancing towards personalised medicine that can improve prognosis and quality of life for patients with these conditions.

A project in close collaboration with patients

This study is possible thanks to the partnership with Hipofam, with whom the team works closely to improve the quality of life of patients with FHHNC. “This project is an example of how collaboration between researchers and patients can change the reality of many rare diseases and advance our understanding of them”, explains Antonio Cabrera, President of Hipofam.