Neuronopathic Gaucher's disease: Induced pluripotent stem cells for disease modelling and testing chaperone activity of small compounds

Gustavo Tiscornia, Erika Lorenzo Vivas, Leslie Matalonga, Ina Berniakovich, Montserrat Barragán Monasterio, Cristina Eguizábal, Laura Gort, Federico González, Carmen Ortiz mellet, José Manuel García Fernández, Antonia Ribes, Anna Veiga, Juan Carlos Izpisua Belmonte*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


Gaucher's disease (GD) is caused by mutations in the GBA1 gene, which encodes acid-β-glucosidase, an enzyme involved in the degradation of complex sphingolipids. While the non-neuronopathic aspects of the disease can be treated with enzyme replacement therapy (ERT), the early-onset neuronopathic form currently lacks therapeutic options and is lethal. We have developed an induced pluripotent stem cell (iPSc) model of neuronopathic GD. Dermal fibroblasts of a patient with a P.[LEU444PRO];[GLY202ARG] genotype were transfected with a loxP-flanked polycistronic reprogramming cassette consisting of Oct4, Sox2, Klf4 and c-Myc and iPSc lines derived. A non-integrative lentiviral vector expressing Cre recombinase was used to eliminate the reprogramming cassette from the reprogrammed cells. Our GD iPSc express pluripotent markers, differentiate into the three germ layers, form teratomas, have a normal karyotype and show the same mutations and low acid-β-glucosidase activity as the original fibroblasts they were derived from. We have differentiated them efficiently into neurons and also into macrophages without observing deleterious effects of the mutations on the differentiation process. Using our system as a platform to test chemical compounds capable of increasing acid-β-glucosidase activity, we confirm that two nojirimycin analogues can rescue protein levels and enzyme activity in the cells affected by the disease.

Original languageEnglish (US)
Pages (from-to)633-645
Number of pages13
JournalHuman Molecular Genetics
Issue number4
StatePublished - Feb 2013
Externally publishedYes

Bibliographical note

Funding Information:
G.T. was partially supported by a Ramon y Cajal fellowship from the Ministry of Education and Science of Spain. Erika Lorenzo Vivas was partially supported by a PFIS fellowship from Instituto de Salud Carlos III, Spain. Leslie Matalonga is a recipient of a grant from BCN-Peptides. This work was supported by Fundacion Cellex, Sanofi, the Spanish Ministerio de Economía y Competitividad (contract numbers SAF2010-15670 and CTQ2010-15848), the Fundación Ramón Areces, the European Union (FEDER and FSE), the Leona M. and Harry B. Helmsley Charitable Trust and the G. Harold and Leila Y. Mathers Charitable Foundation.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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