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Enhancing Lentiviral and Alpharetroviral Transduction of Human Hematopoietic Stem Cells for Clinical Application.
Schott, Juliane W; León-Rico, Diego; Ferreira, Carolina B; Buckland, Karen F; Santilli, Giorgia; Armant, Myriam A; Schambach, Axel; Cavazza, Alessia; Thrasher, Adrian J.
Afiliación
  • Schott JW; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • León-Rico D; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • Ferreira CB; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • Buckland KF; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • Santilli G; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • Armant MA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Schambach A; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Cavazza A; Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
  • Thrasher AJ; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
Mol Ther Methods Clin Dev ; 14: 134-147, 2019 Sep 13.
Article en En | MEDLINE | ID: mdl-31338385
Ex vivo retroviral gene transfer into CD34+ hematopoietic stem and progenitor cells (HSPCs) has demonstrated remarkable clinical success in gene therapy for monogenic hematopoietic disorders. However, little attention has been paid to enhancement of culture and transduction conditions to achieve reliable effects across patient and disease contexts and to maximize potential vector usage and reduce treatment cost. We systematically tested three HSPC culture media manufactured to cGMP and eight previously described transduction enhancers (TEs) to develop a state-of-the-art clinically applicable protocol. Six TEs enhanced lentiviral (LV) and five TEs facilitated alpharetroviral (ARV) CD34+ HSPC transduction when used alone. Combinatorial TE application tested with LV vectors yielded more potent effects, with up to a 5.6-fold increase in total expression of a reporter gene and up to a 3.8-fold increase in VCN. Application of one of the most promising combinations, the poloxamer LentiBOOST and protamine sulfate, for GMP-compliant manufacturing of a clinical-grade advanced therapy medicinal product (ATMP) increased total VCN by over 6-fold, with no major changes in global gene expression profiles or inadvertent loss of CD34+CD90+ HSPC populations. Application of these defined culture and transduction conditions is likely to significantly improve ex vivo gene therapy manufacturing protocols for HSPCs and downstream clinical efficacy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Guideline Idioma: En Revista: Mol Ther Methods Clin Dev Año: 2019 Tipo del documento: Article 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 Tipo de estudio: Guideline Idioma: En Revista: Mol Ther Methods Clin Dev Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos