Efficient expansion and CRISPR-Cas9-mediated gene correction of patient-derived hepatocytes for treatment of inherited liver diseases.
Cell Stem Cell
; 31(8): 1187-1202.e8, 2024 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-38772378
ABSTRACT
Cell-based ex vivo gene therapy in solid organs, especially the liver, has proven technically challenging. Here, we report a feasible strategy for the clinical application of hepatocyte therapy. We first generated high-quality autologous hepatocytes through the large-scale expansion of patient-derived hepatocytes. Moreover, the proliferating patient-derived hepatocytes, together with the AAV2.7m8 variant identified through screening, enabled CRISPR-Cas9-mediated targeted integration efficiently, achieving functional correction of pathogenic mutations in FAH or OTC. Importantly, these edited hepatocytes repopulated the injured mouse liver at high repopulation levels and underwent maturation, successfully treating mice with tyrosinemia following transplantation. Our study combines ex vivo large-scale cell expansion and gene editing in patient-derived transplantable hepatocytes, which holds potential for treating human liver diseases.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Terapia Genética
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Hepatocitos
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Sistemas CRISPR-Cas
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Edición Génica
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Hepatopatías
Límite:
Animals
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Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article