Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts
© 2024 The Authors..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
iScience - 27(2024), 4 vom: 19. Apr., Seite 109530 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nieto-Romero, Virginia [VerfasserIn] |
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| Links: |
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| Themen: |
Biological sciences |
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| Anmerkungen: |
Date Revised 06.04.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.isci.2024.109530 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM37066521X |
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| 520 | |a © 2024 The Authors. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a García-Torralba, Aida |e verfasserin |4 aut | |
| 700 | 1 | |a Molinos-Vicente, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Moya, Francisco José |e verfasserin |4 aut | |
| 700 | 1 | |a Rodríguez-Perales, Sandra |e verfasserin |4 aut | |
| 700 | 1 | |a García-Escudero, Ramón |e verfasserin |4 aut | |
| 700 | 1 | |a Salido, Eduardo |e verfasserin |4 aut | |
| 700 | 1 | |a Segovia, José-Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a García-Bravo, María |e verfasserin |4 aut | |
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