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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2021
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oai:doaj.org-article:7a58ac952d7247cb827b394f9103e9312021-11-20T05:06:45ZEfficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device2329-050110.1016/j.omtm.2021.10.015https://doaj.org/article/7a58ac952d7247cb827b394f9103e9312021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2329050121001728https://doaj.org/toc/2329-0501Hemophilia 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.Cristina OlgasiChiara BorsottiSimone MerlinThorsten BergmannPatrick BittorfAdeolu Badi AdewoyeNicholas WraggKelcey PattersonAndrea CalabriaFabrizio BenedicentiAlessia CucciAlessandra BorchielliniBerardino PollioEugenio MontiniDelfina M. MazzucaMartin ZierauAlexandra StolzingPhilip.M. ToleikisJoris BraspenningAntonia FollenziElsevierarticlehemophilia Acell and gene therapymedical deviceBOEClentiviral vectorFVIIIGeneticsQH426-470CytologyQH573-671ENMolecular Therapy: Methods & Clinical Development, Vol 23, Iss , Pp 551-566 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
hemophilia A cell and gene therapy medical device BOEC lentiviral vector FVIII Genetics QH426-470 Cytology QH573-671 |
| spellingShingle |
hemophilia A cell and gene therapy medical device BOEC lentiviral vector FVIII Genetics QH426-470 Cytology QH573-671 Cristina Olgasi Chiara Borsotti Simone Merlin Thorsten Bergmann Patrick Bittorf Adeolu Badi Adewoye Nicholas Wragg Kelcey Patterson Andrea Calabria Fabrizio Benedicenti Alessia Cucci Alessandra Borchiellini Berardino Pollio Eugenio Montini Delfina M. Mazzuca Martin Zierau Alexandra Stolzing Philip.M. Toleikis Joris Braspenning Antonia Follenzi Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device |
| 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. |
| format |
article |
| author |
Cristina Olgasi Chiara Borsotti Simone Merlin Thorsten Bergmann Patrick Bittorf Adeolu Badi Adewoye Nicholas Wragg Kelcey Patterson Andrea Calabria Fabrizio Benedicenti Alessia Cucci Alessandra Borchiellini Berardino Pollio Eugenio Montini Delfina M. Mazzuca Martin Zierau Alexandra Stolzing Philip.M. Toleikis Joris Braspenning Antonia Follenzi |
| author_facet |
Cristina Olgasi Chiara Borsotti Simone Merlin Thorsten Bergmann Patrick Bittorf Adeolu Badi Adewoye Nicholas Wragg Kelcey Patterson Andrea Calabria Fabrizio Benedicenti Alessia Cucci Alessandra Borchiellini Berardino Pollio Eugenio Montini Delfina M. Mazzuca Martin Zierau Alexandra Stolzing Philip.M. Toleikis Joris Braspenning Antonia Follenzi |
| author_sort |
Cristina Olgasi |
| title |
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_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_sort |
efficient and safe correction of hemophilia a by lentiviral vector-transduced boecs in an implantable device |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/7a58ac952d7247cb827b394f9103e931 |
| work_keys_str_mv |
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| _version_ |
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