Physiopathology studies and therapeutical approaches in animal and cellular models of neurometabolic diseases

Research summary:

The group belongs to CIBER Rare Diseases (CIBERER) and to Health Research Institute Hospital La Paz (IdiPAZ) and actively collaborates with Centro de Diagnóstico de Enfermedades Moleculares (CEDEM, Science Faculty, UAM). Our research is focused in neurometabolic diseases, propionic acidemia (PA) and hyperphenylalaninemias (HPAs) among others, enzymatic deficiencies of autosomal recessive inheritance, characterized by the toxic accumulation of precursors and lack of downstream metabolites.

Our projects represent a translational study with the aim of generating and characterizing animal and cellular models relevant for specific diseases, to be used as research tools to understand the molecular and physiopathological mechanisms responsible for disease,  to analyse potential biomarkers for prognosis and follow-up and to identify new therapeutical targets. The ultimate aim is to develop personalized RNA targeted therapies (antisense oligonucleotides) as well as pharmacological therapies with antioxidant compounds and mitochondrial activators, performing preclinical studies in the specific disease models.

The research group has ample experience in the in vitro and in vivo use of antisense therapy to revert splicing defects in different rare diseases including HPAs, participating in EU-COST Actions within this topic. To date, we are using gene editing CRISPR/Cas9 technology for the generation of cellular and animal models with specific splicing mutations, to identify and test candidate therapeutical antisense oligonucleotides.

Moreover, we are focused on 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 miRNA 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. Of note, we have demonstrated the beneficial effect of antioxidants (resveratrol, MitoQ) both in vitro (patients’ fibroblasts) and in vivo (mouse model) and are currently testing other antioxidants and mitochondrial biogenesis activators. We have generated iPS cells derived from patients’ fibroblasts and differentiated them to neurons and cardiomyocytes, relevant cell lineages for the disease, to perform physiopathological studies and testing of pharmacological and genetic therapies.

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Figure 1. Dysregulated miRNAs identified in the murine model of propionic acidemia and potentially involved in the pathophysiology (adapted from Rivera-Barahona et al. Sci Rep 2017).

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Figure 2. Generation of cardiomyocytes, GABAergic neurons and astrocytes derived from iPSC with propionic acidemia. Differentiation was monitored by immunocytochemistry using antibodies that recognized smooth muscle actin (cardiomyocytes), β-III-tubulin (neurons) and GFAP (astrocytes).

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* For external calls please dial 34 91196 followed by the extension number
Last name Name Laboratory Ext.* e-mail Professional category
Alonso Barroso Esmeralda 220 4596 esmeralda.alonso(at)cbm.csic.es Tit.Sup.Activ.Técn.y Profes. GP1
Álvarez García María del Mar 220 4596 malvarez(at)cbm.csic.es E. Técnicos Superiores Especializados de Organismos Públicos de Investigación
Fulgencio Covián Alejandro 220 4596/7830 alejandro.fulgencio(at)cbm.csic.es Titulado Sup.de Actividades Técn. y Profes. GP1
González Jabalera Pablo 220 4596 Estudiante TFM
Martínez Pizarro Ainhoa 220 4596/7830 ainhoa.martinez(at)cbm.csic.es Tco. de Investigación y Laboratorio
Montalvo de la Prida Elena 220 4596/7830 emontalvo(at)cbm.csic.es Tit.Sup.Activ.Técn.y Profes. GP1
Richard Rodríguez Eva María 220 4628/4596 erichard(at)cbm.csic.es Profesor Titular Universidad, GA
Ruiz Desviat Lourdes 220 4566/7830 lruiz(at)cbm.csic.es Profesor Titular Universidad, GA
Sanchez Lijarcio Obdulia 220 4560/7830 Titulado Sup.de Actividades Técn. y Profes. GP1
Vicente López Rubén 220 4566 Estudiante TFG

Relevant publications:

  • Pathogenic implications of dysregulated miRNAs in propionic acidemia related cardiomyopathy. Fulgencio-Covián A, Alonso-Barroso A, Guenzel AJ, Rivera-Barahona A, Ugarte M, Pérez B, Barry MA, Pérez-Cerdá C, Richard E, Desviat LR*. Transl Res (2020), doi: doi: 10.1016/j.trsl.2019.12.004.
  • Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia. Tamayo M, Fulgencio-Covián A, Navarro-García JA, Val-Blasco A, Ruiz-Hurtado G, Gil-Fernández M, Martín-Nunes L, Lopez JA, Desviat LR, Delgado C, Richard E*, Fernández-Velasco M*. Biochim Biophys Acta Mol Basis Dis. 2020 Jan 1;1866(1):165586. doi: 10.1016/j.bbadis.2019.165586
  • COST Actions: fostering collaborative research for rare diseases. Desviat LR*, Mallebrera CJ, Vallejo-Illarramendi A, Mayán MD, Nogales-Gadea G, Arechavala-Gomeza V. Lancet Neurol. 2019 Nov;18(11):989-991. doi: 10.1016/S1474-4422(19)30366-7.
  • Generation and characterization of a human iPSC line (UAMi004-A) from a patient with propionic acidemia due to defects in the PCCB gene. López-Márquez A, Alonso-Barroso E, Cerro-Tello G, Bravo-Alonso I, Arribas-Carreira L, Briso-Montiano Á, Navarrete R, Pérez-Cerdá C, Ugarte M, Pérez B, Desviat LR, Richard E*. Stem Cell Res. 2019 Jul;38:101469. doi: 10.1016/j.scr.2019.101469.
  • Altered Redox Homeostasis in Branched-Chain Amino Acid Disorders, Organic Acidurias, and Homocystinuria. Richard E, Gallego-Villar L, Rivera-Barahona A, Oyarzábal A, Pérez B, Rodríguez-Pombo P, Desviat LR*. Oxid Med Cell Longev. 2018 Mar 20;2018:1246069. doi: 10.1155/2018/1246069.
  • Intronic PAH gene mutations cause a splicing defect by a novel mechanism involving U1snRNP binding downstream of the 5' splice site. Martínez-Pizarro A, Dembic M, Pérez B, Andresen BS, Desviat LR*. PLoS Genet. 2018 Apr 23;14(4):e1007360. doi: 10.1371/journal.pgen.1007360
  • Generation and characterization of a human iPSC line from a patient with propionic acidemia due to defects in the PCCA gene. Alonso-Barroso E, Brasil S, Briso-Montiano Á, Navarrete R, Pérez-Cerdá C, Ugarte M, Pérez B, Desviat LR, Richard E*. Stem Cell Res. 2017 Aug;23:173-177. doi: 10.1016/j.scr.2017.07.021.
  • Dysregulated miRNAs and their pathogenic implications for the neurometabolic disease propionic acidemia. Rivera-Barahona A, Fulgencio-Covián A, Pérez-Cerdá C, Ramos R, Barry MA, Ugarte M, Pérez B, Richard E, Desviat LR*. Sci Rep. 2017 Jul 18;7(1):5727. doi: 10.1038/s41598-017-06420-8.
  • Delivery is key: lessons learnt from developing splice-switching antisense therapies. Godfrey C, Desviat LR, Smedsrød B, Piétri-Rouxel F, Denti MA, Disterer P, Lorain S, Nogales-Gadea G, Sardone V, Anwar R, El Andaloussi S, Lehto T, Khoo B, Brolin C, van Roon-Mom WM, Goyenvalle A, Aartsma-Rus A, Arechavala-Gomeza V. EMBO Mol Med. 2017 May;9(5):545-557. doi: 10.15252/emmm.201607199.
  • In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: Implications for the pathophysiology of this disorder. Gallego-Villar L, Rivera-Barahona A, Cuevas-Martín C, Guenzel A, Pérez B, Barry MA, Murphy MP, Logan A, Gonzalez-Quintana A, Martín MA, Medina S, Gil-Izquierdo A, Cuezva JM, Richard E, Desviat LR*. Free Radic Biol Med. 2016 Jul;96:1-12. doi: 10.1016/j.freeradbiomed.2016.04.007

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