Your browser doesn't support javascript.
loading
Adenine base editing reduces misfolded protein accumulation and toxicity in alpha-1 antitrypsin deficient patient iPSC-hepatocytes.
Werder, Rhiannon B; Kaserman, Joseph E; Packer, Michael S; Lindstrom-Vautrin, Jonathan; Villacorta-Martin, Carlos; Young, Lauren E; Aratyn-Schaus, Yvonne; Gregoire, Francine; Wilson, Andrew A.
Afiliación
  • Werder RB; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
  • Kaserman JE; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
  • Packer MS; Beam Therapeutics, Cambridge, MA 02139, USA.
  • Lindstrom-Vautrin J; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA.
  • Villacorta-Martin C; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA.
  • Young LE; Beam Therapeutics, Cambridge, MA 02139, USA.
  • Aratyn-Schaus Y; Beam Therapeutics, Cambridge, MA 02139, USA.
  • Gregoire F; Beam Therapeutics, Cambridge, MA 02139, USA.
  • Wilson AA; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: awilson@bu.edu.
Mol Ther ; 29(11): 3219-3229, 2021 11 03.
Article en En | MEDLINE | ID: mdl-34217893
Alpha-1 antitrypsin deficiency (AATD) is most commonly caused by the Z mutation, a single-base substitution that leads to AAT protein misfolding and associated liver and lung disease. In this study, we apply adenine base editors to correct the Z mutation in patient induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iHeps). We demonstrate that correction of the Z mutation in patient iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base editing (ABE) of differentiated iHeps decreases ER stress in edited cells, as demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in iPSCs and do not identify off-target genomic mutations by whole-genome sequencing. These results reveal the feasibility and utility of base editing to correct the Z mutation in AATD patient cells.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenina / Alfa 1-Antitripsina / Deficiencia de alfa 1-Antitripsina / Hepatocitos / Células Madre Pluripotentes Inducidas / Sistemas CRISPR-Cas / Edición Génica Límite: Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenina / Alfa 1-Antitripsina / Deficiencia de alfa 1-Antitripsina / Hepatocitos / Células Madre Pluripotentes Inducidas / Sistemas CRISPR-Cas / Edición Génica Límite: Humans Idioma: En Revista: Mol Ther Asunto de la revista: BIOLOGIA MOLECULAR / TERAPEUTICA Año: 2021 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos