Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts.

Autor:	Nieto-Romero V; Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain., García-Torralba A; Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain., Molinos-Vicente A; Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain., Moya FJ; Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain., Rodríguez-Perales S; Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain., García-Escudero R; Molecular Oncology Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)-ISCIII, Research Institute Hospital 12 de Octubre (imas12)-University Hospital 12 de Octubre, 28040 Madrid, Spain., Salido E; Pathology Department, Hospital Universitario de Canarias, Universidad La Laguna, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, 38320 Tenerife, Spain., Segovia JC; Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain., García-Bravo M; Cell Technology Division, Biomedical Innovation Unit, CIEMAT (Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 Mar 21; Vol. 27 (4), pp. 109530. Date of Electronic Publication: 2024 Mar 21 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.109530
Abstrakt:	Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused by mutations in the AGXT gene. Combined liver and kidney transplantation is currently the only permanent curative treatment. We combined locus-specific gene correction and hepatic direct cell reprogramming to generate autologous healthy induced hepatocytes (iHeps) from PH1 patient-derived fibroblasts. First, site-specific AGXT corrected cells were obtained by homology directed repair (HDR) assisted by CRISPR-Cas9, following two different strategies: accurate point mutation (c.731T>C) correction or knockin of an enhanced version of AGXT cDNA. Then, iHeps were generated, by overexpression of hepatic transcription factors. Generated AGXT -corrected iHeps showed hepatic gene expression profile and exhibited in vitro reversion of oxalate accumulation compared to non-edited PH1-derived iHeps. This strategy set up a potential alternative cellular source for liver cell replacement therapy and a personalized PH1 in vitro disease model. Competing Interests: The authors declare no competing interests. (© 2024 The Authors.)
Databáze:	MEDLINE
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