Friday, 6th December 2019

Translational medicine in inborn errors of metabolism and other rare genetic diseases





Belén Pérez González






Research summary:

Inborn errors of metabolism (IEM) are a large group of rare genetic diseases, including any condition in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease. Nevertheless many of them detected by standard biochemical test are not genetically solved. In addition, many of them lack a definitive therapy. In this context, our objectives, aligned with the worldwide aims in translational research in rare diseases, are addressed to improve the knowledge of IEM towards tailored treatments. First, our activity is aimed to the identification of new genes causing pathology using a combination of "omics" tools (genomic, transcriptomic and metabolomic technologies) and cellular biology techniques, in order to decipher the effect of altered genes and to identify novel pathological processes. Specifically, we are working on the identification and characterization of genetic defects involved in the process of glycosylation and protein transport (CDG syndrome), as well as in other diseases related to mitochondrial dysfunction or neurological disorders due to cerebral glucose transport deficiency, among others. We are also involved in the development of specific therapeutic strategies targeted to the mechanism of action of the mutations detected in neurometabolic diseases in the era of the personalized medicine. To that end, we are specifically involved in the development of therapies designed to rescue defects affecting protein folding, an extended mechanism in many IEM. For preclinical studies and for searching additional therapeutic targets based on pathophysiology studies we are working in the generation of disease cellular models obtained from reprogramming of patient derived fibroblasts and subsequent differentiation into hepatocytes, neurons or other tissues more relevant to the disease. In a later preclinical stage we intend also to use hepatic and cerebellar organoids to validate the potential drugs before testing in the adequate animal models.

This project is funded by the following grants: ISCIII (PI16/00573), CIBERER (ER18TRL746), Comunidad de Madrid (B2017/BMD3721) y Fundación Isabel Gemio in collaboration with La Obra Social de la Caixa (LCF/PR/PR16/11110018).

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Relevant publications:

  • New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type. BBA, Molecular Basis of Disease(2018) 1864(2):640-648.
  • Generation and characterization of two human iPSC lines from patients with methylmalonic acidemia cblB type. Stem Cell Research (2018) 29:143-147.
  • Protein misfolding diseases: prospects of pharmacological treatment. Clin Genet. 2017 Jul 3. doi: 10.1111/cge.13088. Review.
  • A Population-Based Study on Congenital Disorders of Protein N- and Combined with O-Glycosylation Experience in Clinical and Genetic Diagnosis. J Pediatr. 2017 Apr;183:170-177.
  • Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease. Hum Mutat. 2017 Jun;38(6):678-691. doi: 10.1002/humu.23208. Epub 2017 Mar 20.
  • Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG. Hum Mutat. 2017 Feb;38(2):160-168. doi: 10.1002/humu.23138. Epub 2016 Nov 21.
  • Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing. Genet Med. 2016 Oct;18(10):1037-43. doi: 10.1038/gim.2015.217.
  • Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1862 (4), pp. 592-600.
  • Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II. Biochim Biophys Acta. 2015 Dec;1852(12):2712-21. doi: 10.1016/j.bbadis.2015.09.011. Epub 2015 Sep 25.
  • The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein.Hum Mutat. Hum Mutat. 2015 Sep;36(9):851-60. doi: 10.1002/humu.22817.

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