Cabecera CBMSO CSIC UAM

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 

DSciStaff

DPublications

 

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, www.cbm.uam.es/cedem). 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.

figura1

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)

figura2

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

 

NOTE! This site uses cookies and similar technologies.

If you not change browser settings, you agree to it. Learn more

I understand

COOKIES POLICY

What are cookies?

A cookie is a file that is downloaded to your computer when you access certain web pages. Cookies allow a web page, among other things, to store and retrieve information about the browsing habits of a user or their equipment and, depending on the information they contain and the way they use their equipment, they can be used to recognize the user.

Types of cookies

Classification of cookies is made according to a series of categories. However, it is necessary to take into account that the same cookie can be included in more than one category.

  1. Cookies according to the entity that manages them

    Depending on the entity that manages the computer or domain from which the cookies are sent and treat the data obtained, we can distinguish:

    • Own cookies: those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which the service requested by the user is provided.
    • Third party cookies: those that are sent to the user's terminal equipment from a computer or domain that is not managed by the publisher, but by another entity that processes the data obtained through the cookies. When cookies are installed from a computer or domain managed by the publisher itself, but the information collected through them is managed by a third party, they cannot be considered as own cookies.

  2. Cookies according to the period of time they remain activated

    Depending on the length of time that they remain activated in the terminal equipment, we can distinguish:

    • Session cookies: type of cookies designed to collect and store data while the user accesses a web page. They are usually used to store information that only is kept to provide the service requested by the user on a single occasion (e.g. a list of products purchased).
    • Persistent cookies: type of cookies in which the data is still stored in the terminal and can be accessed and processed during a period defined by the person responsible for the cookie, which can range from a few minutes to several years.

  3. Cookies according to their purpose

    Depending on the purpose for which the data obtained through cookies are processed, we can distinguish between:

    • Technical cookies: those that allow the user to navigate through a web page, platform or application and the use of different options or services that exist in it, such as controlling traffic and data communication, identifying the session, access to restricted access parts, remember the elements that make up an order, perform the purchase process of an order, make a registration or participation in an event, use security elements during navigation, store content for the broadcast videos or sound or share content through social networks.
    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers: