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project info
Start date: 1 January 2015
End date: 31 August 2018
funding
Fund: European Regional Development Fund (ERDF)
Total budget: 181 500,00 €
EU contribution: 98 826,75 € (54,45%)
programme
Programming period: 2014-2020
Managing authority: Subdirección General de Gestión del FEDER, de la Dirección General de Fondos Europeos del Ministerio de Hacienda.
European Commission Topic

NEW STRATEGY FOR THE DERIVATION OF FUNCTIONAL HEPATOCYTES IN WOMEN AFFECTED BY TRANSCARBAMILASE ORNITHINE DEFICIENCY

TRANSCARBAMILASE ORNITHINE DEFICIENCY (OTC; OMIM#311250; XP21.1) IS A RARE METABOLIC DISEASE OF THE UREA CYCLE LINKED TO THE X CHROMOSOME THAT CAUSES HYPERAMMONIA. THE DISEASE CAN DEVELOP ASYMPTOMATIC OR IN SEVERE CASES LEAD TO VERY SEVERE SYMPTOMATOLOGY AT VERY EARLY AGES AND EVEN PERINATAL DEATH. AT PRESENT THERE IS NO TREATMENT BEYOND HEPATIC TRANSPLANTATION, WHICH IN THE CASE OF PEDIATRIC PATIENTS IS NOT A SOLUTION DUE TO THE HIGH MORBIDITY-MORTALITY OF IMMUNOSUPPRESSIVE TREATMENTS. ALL OF THIS MAKES THIS DISEASE A GOOD CANDIDATE FOR ADVANCED CELL THERAPIES. THIS PROJECT PROPOSES PROOF OF CONCEPT THAT IT IS POSSIBLE TO DERIVE HEALTHY HEPATOCYTES FROM WOMEN AFFECTED BY OTC DEFICIENCY WITHOUT THE NEED FOR GENE-EDITING. Our approach is to promote the silencing of chromosome X in women or lionisation._x000D_ WOMEN are in a real quality of a CELULAR MOSAIC in which all CELULAS expresive the chromosomal X MATERN and other PATERN. THE LIVER OF WOMEN (HETEROZYGOTES) AFFECTED BY OTC DEFICIENCY IS COMPOSED ALMOST EXCLUSIVELY OF HEPATOCYTES THAT HAVE SILENCED THE X CHROMOSOME CONTAINING THE WILD (FUNCTIONAL) ALLELE OF OTC. OUR STRATEGY IS TO ISOLATE NUCLEATED CELLS (FIBROBLASTS AND URINARY EPITHELIUM CELLS PRESENT IN URINE) FROM PATIENTS AFFECTED BY OTC DEFICIENCY, OBTAIN HOMOGENEOUS CULTURES OF CELLS THAT HAVE SILENCED THE X CHROMOSOME CONTAINING THE MUTATED ALLELE AND REPROGRAM THEM TO HEPATOCYTES. This STRATEGY CAN BE EXTENSIVE TO OTHER DISEASES LIGED TO CHROMOSOME X as hemophilia A and B._x000D_ METHOD VENTAJA IS EVITING GENOMIC MANIPUATION (GENE-EDITING IN ENGLES) THAT IS EXTRAORDINARY COMPLETED AND ALWAYS CAN lead to proceedings undesired and Potentially GRAVED BY OFF-targeting Phenomenons. LIKEWISE, AS A BY-PRODUCT OF THIS PROJECT WE WILL OBTAIN HEPATOCYTES WITH OTC DEFICIENCY AS AN IN VITRO MODEL TO DEEPEN THE METABOLIC ASPECTS OF THE DISEASE AND FOR THE DEVELOPMENT OF PALLIATIVE PHARMACOS.

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