The Inocente Inocente Foundation has granted €21,000 to fund a project of the Vall d'Hebron Research Institute (VHIR) that aims to study the functional impact of phenotype-modifying genetic variants in patients suffering from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (HFHNC), with the aim of improving diagnosis and developing new therapeutic solutions.

The research is part of the 'Futuro Magnéfico' project led by the Hipofam association. The programme also has an assistance component aimed at covering the financial costs of children with hereditary hypomagnesaemia. In total, the Inocente Inocente Foundation has given €25,000 for the two initiatives, which will represent 24% of the research budget and 42% of the assistance part.

To understand the causes that lead to more rapid disease progression in patients with the same mutation.

HFHNC is an ultra-rare kidney disease, with an incidence of less than one person per million population. It is caused by mutations in the genes coding for claudin 16 (CLDN16) and claudin 19 (CLDN19), the latter mutation being the most prevalent among the Spanish population affected by this pathology. Affected individuals suffer an inexorable progression towards chronic kidney disease and renal replacement therapy (dialysis and transplantation) early in life. Congenital eye defects that limit vision to varying degrees are also characteristic. At present, there is no specific treatment for this disease, with only supporting therapies.

The large phenotypic variability found among patients, even among those with the same mutation in CLDN19 (p.G20D in homozygosis) and among members of the same family, suggests the existence of other genetic, epigenetic and/or environmental factors that could be modulating the severity and progression of the disease.

Through a whole exome analysis (WES) of Spanish patients, the Renal Pathophysiology group at VHIR, led by Dr. Anna Meseguer, has identified 17 genetic variants associated with very aggressive phenotypes that could explain, in part, the rapid loss of kidney function in patients who require a transplant before reaching age 5.

To understand how the combination of the p.G20D mutation with some of these variants leads to the most severe manifestation of the disease, the generation of induced pluripotent stem cells (iPSCs) from the skin cells of two siblings who, despite having the same mutation, show marked differences in disease progression has been proposed. Stem cells from both siblings will be reprogrammed into kidney cells and, using the CRISPR/Cas9 gene-editing technique, different cell lines will be generated containing or not the disease-causing mutation in combination with three of the most promising genetic variants present only in the patient with the severe phenotype. Organoids will then be produced from these patient-derived cell lines to reproduce as closely as possible what happens in the kidney of HFHNC patients.

The team, which includes Dr. Gema Ariceta, head of the Paediatric Nephrology Service, principal investigators Dr. Cristina Martínez and Dr. Gerard Cantero, as well as PhD student Julieta Torchia, among others, anticipates that the results will improve knowledge of the pathophysiology of the disease and also promote the design of new diagnostic and therapeutic approaches to prevent the progression of HFHNC to end-stage renal disease. Dr. Anna Meseguer, head of the Renal Pathophysiology group, adds "our research will not only be a breakthrough for patients with HFHNC and their families, but also for those with other renal pathologies with a similar clinical progression, such as Dent's disease, thus broadening the scope of the population that will benefit".

The hope of obtaining a specific treatment

The Hipofam association is very pleased to be able to contribute to research into this disease by helping VHIR. They highlight the partnership created between the association, patients and the research team of the renal physiopathology research group over the last 9 years, which has allowed to advance in the knowledge of the disease thanks to everyone's efforts.

Antonio Cabrera, president of the association explains that "The outlook we have and the hope of finding a treatment has changed a lot in these 9 years because before there was no line of research in place and now with the experience we have gained, we know that it is a matter of time, that it is still a long way off and that it will not be easy, but now we do believe that it will be possible to obtain treatments that will slow down the progression of the disease". He adds that "The line of research that will begin with this donation is very innovative and opens up a whole range of possibilities that excites us even more. We are convinced that results will be achieved that will ultimately have an impact on patients, and therefore we will continue to support the work of VHIR, trusting in its great professionalism, involvement and human quality".

In addition to the Hipofam association, the project has the involvement of Anaxomics Biotech, which is the company responsible for the generation of mathematical models for drug identification, and the National Bank of Cell Lines, which is part of the ISCIII Platforms to support R&D in Biomedicine.