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Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device

Hemophilia A (HA) is a rare bleeding disorder caused by deficiency/dysfunction of the FVIII protein. As current therapies based on frequent FVIII infusions are not a definitive cure, long-term expression of FVIII in endothelial cells through lentiviral vector (LV)-mediated gene transfer holds the pr...

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Autores principales: Olgasi, Cristina, Borsotti, Chiara, Merlin, Simone, Bergmann, Thorsten, Bittorf, Patrick, Adewoye, Adeolu Badi, Wragg, Nicholas, Patterson, Kelcey, Calabria, Andrea, Benedicenti, Fabrizio, Cucci, Alessia, Borchiellini, Alessandra, Pollio, Berardino, Montini, Eugenio, Mazzuca, Delfina M., Zierau, Martin, Stolzing, Alexandra, Toleikis, Philip.M., Braspenning, Joris, Follenzi, Antonia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606349/
https://www.ncbi.nlm.nih.gov/pubmed/34853801
http://dx.doi.org/10.1016/j.omtm.2021.10.015
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author Olgasi, Cristina
Borsotti, Chiara
Merlin, Simone
Bergmann, Thorsten
Bittorf, Patrick
Adewoye, Adeolu Badi
Wragg, Nicholas
Patterson, Kelcey
Calabria, Andrea
Benedicenti, Fabrizio
Cucci, Alessia
Borchiellini, Alessandra
Pollio, Berardino
Montini, Eugenio
Mazzuca, Delfina M.
Zierau, Martin
Stolzing, Alexandra
Toleikis, Philip.M.
Braspenning, Joris
Follenzi, Antonia
author_facet Olgasi, Cristina
Borsotti, Chiara
Merlin, Simone
Bergmann, Thorsten
Bittorf, Patrick
Adewoye, Adeolu Badi
Wragg, Nicholas
Patterson, Kelcey
Calabria, Andrea
Benedicenti, Fabrizio
Cucci, Alessia
Borchiellini, Alessandra
Pollio, Berardino
Montini, Eugenio
Mazzuca, Delfina M.
Zierau, Martin
Stolzing, Alexandra
Toleikis, Philip.M.
Braspenning, Joris
Follenzi, Antonia
author_sort Olgasi, Cristina
collection PubMed
description Hemophilia A (HA) is a rare bleeding disorder caused by deficiency/dysfunction of the FVIII protein. As current therapies based on frequent FVIII infusions are not a definitive cure, long-term expression of FVIII in endothelial cells through lentiviral vector (LV)-mediated gene transfer holds the promise of a one-time treatment. Thus, here we sought to determine whether LV-corrected blood outgrowth endothelial cells (BOECs) implanted through a prevascularized medical device (Cell Pouch) would rescue the bleeding phenotype of HA mice. To this end, BOECs from HA patients and healthy donors were isolated, expanded, and transduced with an LV carrying FVIII driven by an endothelial-specific promoter employing GMP-like procedures. FVIII-corrected HA BOECs were either directly transplanted into the peritoneal cavity or injected into a Cell Pouch implanted subcutaneously in NSG-HA mice. In both cases, FVIII secretion was sufficient to improve the mouse bleeding phenotype. Indeed, FVIII-corrected HA BOECs reached a relatively short-term clinically relevant engraftment being detected up to 16 weeks after transplantation, and their genomic integration profile did not show enrichment for oncogenes, confirming the process safety. Overall, this is the first preclinical study showing the safety and feasibility of transplantation of GMP-like produced LV-corrected BOECs within an implantable device for the long-term treatment of HA.
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spelling pubmed-86063492021-11-30 Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device Olgasi, Cristina Borsotti, Chiara Merlin, Simone Bergmann, Thorsten Bittorf, Patrick Adewoye, Adeolu Badi Wragg, Nicholas Patterson, Kelcey Calabria, Andrea Benedicenti, Fabrizio Cucci, Alessia Borchiellini, Alessandra Pollio, Berardino Montini, Eugenio Mazzuca, Delfina M. Zierau, Martin Stolzing, Alexandra Toleikis, Philip.M. Braspenning, Joris Follenzi, Antonia Mol Ther Methods Clin Dev Original Article Hemophilia A (HA) is a rare bleeding disorder caused by deficiency/dysfunction of the FVIII protein. As current therapies based on frequent FVIII infusions are not a definitive cure, long-term expression of FVIII in endothelial cells through lentiviral vector (LV)-mediated gene transfer holds the promise of a one-time treatment. Thus, here we sought to determine whether LV-corrected blood outgrowth endothelial cells (BOECs) implanted through a prevascularized medical device (Cell Pouch) would rescue the bleeding phenotype of HA mice. To this end, BOECs from HA patients and healthy donors were isolated, expanded, and transduced with an LV carrying FVIII driven by an endothelial-specific promoter employing GMP-like procedures. FVIII-corrected HA BOECs were either directly transplanted into the peritoneal cavity or injected into a Cell Pouch implanted subcutaneously in NSG-HA mice. In both cases, FVIII secretion was sufficient to improve the mouse bleeding phenotype. Indeed, FVIII-corrected HA BOECs reached a relatively short-term clinically relevant engraftment being detected up to 16 weeks after transplantation, and their genomic integration profile did not show enrichment for oncogenes, confirming the process safety. Overall, this is the first preclinical study showing the safety and feasibility of transplantation of GMP-like produced LV-corrected BOECs within an implantable device for the long-term treatment of HA. American Society of Gene & Cell Therapy 2021-11-03 /pmc/articles/PMC8606349/ /pubmed/34853801 http://dx.doi.org/10.1016/j.omtm.2021.10.015 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Olgasi, Cristina
Borsotti, Chiara
Merlin, Simone
Bergmann, Thorsten
Bittorf, Patrick
Adewoye, Adeolu Badi
Wragg, Nicholas
Patterson, Kelcey
Calabria, Andrea
Benedicenti, Fabrizio
Cucci, Alessia
Borchiellini, Alessandra
Pollio, Berardino
Montini, Eugenio
Mazzuca, Delfina M.
Zierau, Martin
Stolzing, Alexandra
Toleikis, Philip.M.
Braspenning, Joris
Follenzi, Antonia
Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device
title Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device
title_full Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device
title_fullStr Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device
title_full_unstemmed Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device
title_short Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device
title_sort efficient and safe correction of hemophilia a by lentiviral vector-transduced boecs in an implantable device
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606349/
https://www.ncbi.nlm.nih.gov/pubmed/34853801
http://dx.doi.org/10.1016/j.omtm.2021.10.015
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