Friday, 6th December 2019

Molecular bases of inherited metabolic diseases and research in molecular therapies

 2017 02 07 Grupo Lourdes RuizDesviat 02 400px


Lourdes Ruiz Desviat 




Research summary:

The group belongs to the Biomedical Network Research Centre for Rare Diseases (CIBERER) and to Hospital La Paz Institute for Health Research (IdiPaz) and collaborates actively with Centro de Diagnóstico de Enfermedades Moleculares (CEDEM, Facultad de Ciencias, UAM, Our work is focused on the research on the molecular basis of different inherited metabolic diseases (IMD), of their cellular pathophysiology and of the molecular mechanism of mutations identified in patients with the aim of identifying therapeutic targets and developing new genetic and pharmacological treatment strategies. New genomic technologies based on arrays and whole exome sequencing have been implemented for gene identification and mutation detection in IMD. Gene capture and exome enrichment strategies for genes responsible for specific diseases are being validated for genetic diagnosis. We have recently published the identification of novel regulatory defects in the multienzymatic mitochondrial complex BCKDH involved in disease.


Figure 1: Antisense oligonucleotide treatment in Pahenu2/+ mice. (A) Mice were treated with i.v. injections with VMO-ex11 at the indicated doses and sacrificed at day 4 after the first injection. (B) Blood L-Phe levels, (C) RT-PCR analysis of Pah-mRNA from liver, and (D) Western blot analysis showing PAH protein levels in liver. (E) PAH enzyme activity relative to control wild-type levels. (Gallego-Villar et al. 2014)


Figure 2: Generation and characterization of MMA cblB type patient-specific iPSC lines. A). Patient iPSC stained for alkaline phosphatase activity. B). Normal karyotype of patient iPS cell line. C-F). Representative colonies of patient iPSC stained positive for the pluripotency-associated markers. G-I). Immunofluorescence analysis of iPSC differentiated in vitro showing the potential to generate cell derivatives of all three primary germ cell layers. J). Metahylatin analysis of the OCT4 promoter by bisulphite sequencing. K). Direct sequenced of genomic DNA from patient iPSC identifying the mutations.


In our research we use conventional protein expression systems, both prokaryotic and eukaryotic, as well as patients' cells and murine models of disease. We have generated iPS cells derived from patients' fibroblasts to further differentiate them into hepatocytes, neural precursors and/or cardiomyocytes, cellular lineages relevant in the corresponding disease, for future physiopathology studies and analysis of therapeutical approaches. We have characterized the effect of mutations identified in patients on the splicing, translation and folding processes of genes and protein describing several new molecular targets for therapeutic intervention, in the field of what is known as personalized genetic medicine. The group has developed a gene specific antisense RNA-based therapy for splicing defects in a number of IMD and developed a murine assay system for in vivo validation of the approach. We have established the proof-of-concept of the therapeutic use of readthrough drugs for nonsense mutation suppression in organic acidurias. For missense mutations affecting protein folding and stability novel compounds with chaperone activity have been identified as potential treatment for methylmalonic aciduria, some of which have been patented, and for congenital glycosylation defects. We are also working on the cellular processes involved in the pathophysiology of the disease such as mitochondrial dysfunction and endoplasmic reticulum stress. We have analyzed the mitochondrial dysfunction present in several diseases revealing secondary respiratory chain defects and increased ROS levels which could be targets for drugs acting on the restoration of the mitochondrial homeostasis. In addition, we are also analyzing the role of miRNA in the pathophysiology of propionic acidemia.


Relevant publications:

- 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,DesviatLR, Richard E.
Stem Cell Res. 2017 Aug;23:173-177.

- 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,DesviatLR.
Sci Rep. 2017 Jul 18;7(1):5727.

- 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.

- New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type.
Brasil S, Briso-Montiano A, Gámez A, Underhaug J, Flydal MI, Desviat L, Merinero B, Ugarte M, Martinez A, Pérez B.
Biochim Biophys Acta Mol Basis Dis. 2018 Feb;1864(2):640-648.

- 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.

- Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.
Bravo-Alonso I, Navarrete R, Arribas-Carreira L, Perona A, Abia D, Couce ML, García-Cazorla A, Morais A, Domingo R, Ramos MA, Swanson MA, Van Hove JLK, Ugarte M, Pérez B, Pérez-Cerdá C, Rodríguez-Pombo P.
Hum Mutat. 2017 Jun;38(6):678-691


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