The research group has ample experience in the generation of iPSCs from patients’ fibroblasts and their differentiation to neuronal precursors, astrocytes and cardiomyocytes, relevant cell lineages for the diseases under study. We have also extensively used gene editing CRISPR/Cas9 technology to generate cellular (hepatoma cells, iPSCs) and animal (mouse) models of disease, both knock-out or knock-in with patient specific mutations.
One line of research involves the analysis of the physiopathological mechanisms underlying PA, one of the most frequent organic acidemias in which we have demonstrated, using a mouse model, that mitochondrial dysfunction, oxidative stress and miRNAs dysregulation contribute to the multiorganic complications of the disease. We have revealed alterations in Ca2+ mishandling, associated to elevated ROS levels and higher SERCA2a oxidation rate, along with dysregulation of specific cardiomiRs, as mechanisms involved in the development of PA associated cardiomyopathies. Studies in iPSCs-derived cardiomyocytes confirm these alterations, with PA cardiomyocytes exhibiting greatly depressed cell excitability and an increased risk of arrythmias. In iPSCs-derived PA astrocytes we observe altered mitochondrial function, miRNAs deregulation and astrogliosis.

For many years the group has studied the molecular genetics of different inherited metabolic diseases, with a special emphasis on missense and splicing variants. We have characterized the molecular mechanism of many of these variants using different eukaryotic and prokaryotic expression systems and splicing reporter minigenes. We have developed methods for modulation of splicing using antisense oligonucleotides, having successfully corrected splicing defects in cellular models of different diseases. Ongoing studies involve the use of gene editing approaches (CRISPR/Cas, base editors) to permanently correct in vitro and in vivo specific variants casing inherited metabolic diseases.