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iPSC-Derived Intestinal Organoids from Cystic Fibrosis Patients Acquire CFTR Activity upon TALEN-Mediated Repair of the p.F508del Mutation.
Fleischer, Aarne; Vallejo-Díez, Sara; Martín-Fernández, José María; Sánchez-Gilabert, Almudena; Castresana, Mónica; Del Pozo, Angel; Esquisabel, Amaia; Ávila, Silvia; Castrillo, José Luis; Gaínza, Eusebio; Pedraz, José Luis; Viñas, Miguel; Bachiller, Daniel.
Afiliación
  • Fleischer A; Karuna Good Cells Technologies S.L., C/Cercas Bajas 13 Bajo, 01001 Vitoria-Gasteiz, Spain.
  • Vallejo-Díez S; Consejo Superior de Investigaciones Científicas (CSIC/IMEDEA), Miguel Marqués 21, 07190 Esporles, Spain.
  • Martín-Fernández JM; Karuna Good Cells Technologies S.L., C/Cercas Bajas 13 Bajo, 01001 Vitoria-Gasteiz, Spain.
  • Sánchez-Gilabert A; Karuna Good Cells Technologies S.L., C/Cercas Bajas 13 Bajo, 01001 Vitoria-Gasteiz, Spain.
  • Castresana M; Karuna Good Cells Technologies S.L., C/Cercas Bajas 13 Bajo, 01001 Vitoria-Gasteiz, Spain.
  • Del Pozo A; Biokeralty, C/Arkaute, 5, 01192 Vitoria-Gasteiz, Spain.
  • Esquisabel A; NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
  • Ávila S; Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
  • Castrillo JL; Genetadi Biotech S.L., Parque Tecnológico de Bizkaia, 48160 Derio, Spain.
  • Gaínza E; Genetadi Biotech S.L., Parque Tecnológico de Bizkaia, 48160 Derio, Spain.
  • Pedraz JL; Biokeralty, C/Arkaute, 5, 01192 Vitoria-Gasteiz, Spain.
  • Viñas M; NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain.
  • Bachiller D; Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
Mol Ther Methods Clin Dev ; 17: 858-870, 2020 Jun 12.
Article en En | MEDLINE | ID: mdl-32373648
ABSTRACT
Cystic fibrosis (CF) is the main genetic cause of death among the Caucasian population. The disease is characterized by abnormal fluid and electrolyte mobility across secretory epithelia. The first manifestations occur within hours of birth (meconium ileus), later extending to other organs, generally affecting the respiratory tract. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encodes a cyclic adenosine monophosphate (cAMP)-dependent, phosphorylation-regulated chloride channel required for transport of chloride and other ions through cell membranes. There are more than 2,000 mutations described in the CFTR gene, but one of them, phenylalanine residue at amino acid position 508 (p.F508del), a recessive allele, is responsible for the vast majority of CF cases worldwide. Here, we present the results of the application of genome-editing techniques to the restoration of CFTR activity in p.F508del patient-derived induced pluripotent stem cells (iPSCs). Gene-edited iPSCs were subsequently used to produce intestinal organoids on which the physiological activity of the restored gene was tested in forskolin-induced swelling tests. The seamless restoration of the p.F508del mutation resulted in normal expression of the mature CFTR glycoprotein, full recovery of CFTR activity, and a normal response of the repaired organoids to treatment with two approved CF therapies VX-770 and VX-809.
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Texto completo: 1 Base de datos: MEDLINE Idioma: En Revista: Mol Ther Methods Clin Dev Año: 2020 Tipo del documento: Article País de afiliación: España

Texto completo: 1 Base de datos: MEDLINE Idioma: En Revista: Mol Ther Methods Clin Dev Año: 2020 Tipo del documento: Article País de afiliación: España