Saturday, 23rd June 2018

 Molecular Neuropathology

        Neurometabolic disorders: Research on splicing therapies                                                       and pharmacological chaperones.






Belén Pérez González







Research summary:

Belen Perez is the head of the group U746 at the Biomedical Network Research Centre for Rare Diseases (CIBERER) and the group 45 at the Biomedical Research Institute (IDIPAZ). Our projects are focused on the genetic characterization of neurometabolic disorders as first step to the identification of new therapeutic targets and therapeutic strategies addressed to improve the current treatments. The current projects are focused to improve the genetic diagnosis of metabolic disorders by cellular exome sequencing in order to identify new disease-causing genes on congenital disorders of glycosylation, a highly heterogeneous disorder, and methylmalonic aciduria patients. Second, the project are aimed to generate new disease cellular models by reprograming of patient-specific induced pluripotent stem cells (iPS) to neuron and liver cells differentiated from MUT, MMAB and PMM2 patient-derived fibroblasts for disease modeling, drug testing and drug discovery in tissues more relevant for the disease. Furthermore the projects are focused to investigate mRNA and protein therapeutic approaches. Specifically, we are seeking pharmacological chaperones (PC) to rescue destabilizing mutations detected in MMA and PMM2 affected-patients and antisense therapy targeted to rescue exonic and intronic cryptic splice site mutations. The PC are been sought by computational approaches using the software SEE-Tx™ develop by Minoryx and by high-throughput screening of a commercial library. After, different biological approaches will be used to evaluate the effect of selected hits on stability, activity and toxicity. The project will be complement by analysis of drug repositioning for finding novel indications for existing drugs.

European Regional Development Fund (FEDER) grant IPT-2012-0561-010000 and grant from Isciii PI13/01239. Ministerio de Economia y Competitividad.


Relevant publications:

  1. Pharmacological chaperones as a potential therapeutic option in methylmalonic aciduria cblB type. Jorge-Finnigan A, S Brasil, S Underhaug, Ruiz-Sala P, Merinero B, Banerjee R, Desviat LR, Ugarte M, Martinez A, Perez B. Human Molecular Genetics Sep 15;22(18):3680-9. (2013).
  2. Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin deficient hyperphenylalaninemias by high-throughput targeted sequencing. Daniel Trujillano, Belén Perez, Justo González, Cristian TornadorRosa Navarrete, Georgia Escaramis, Stephan Ossowski, Lluís Armengol, Verónica Cornejo, Lourdes R Desviat, Magdalena Ugarte and Xavier Estivill*. Eur J Hum Genet. 2013 ( in press)
  3. Clinical Biochemical and molecular studies in pyridoxine-dependent epilepsy. Antisense therapy as possible new therapeutic option. Belén Pérez*, Luis González Gutiérrez-Solana, Alfonso Verdú, Begoña Merinero,Patricia Yuste-Checa,Pedro Ruiz-Sala, Rocio Calvo, Anil Jalan, Laura López Marín, Oscar Campos, Maria Ángeles Ruiz, Marta San Miguel, Maria Vázquez, Margarita Castro, Isaac Ferrer, Rosa Navarrete, Lourdes Ruiz Desviat, Pablo Lapunzina,Magdalena Ugarteand Celia Pérez-Cerdá. Epilepsia 2013 Feb; 54(2):239-48
  4. A novel congenital disorder of glycosylation subtype without central nervous system involvement caused by mutations in the phosphoglucomutase 1 gen. Belén Pérez1, Celia Medrano1, Maria Jesus Ecay1, Pedro Ruiz-Sala1, Mercedes Martínez-Pardo2, Magdalena Ugarte1 and Celia Pérez-Cerdá1*. J Inherit Metab Dis. 2013 May;36(3):535-42.