Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device.
BOEC
FVIII
cell and gene therapy
endothelial cells
hemophilia A
lentiviral vector
medical device
Journal
Molecular therapy. Methods & clinical development
ISSN: 2329-0501
Titre abrégé: Mol Ther Methods Clin Dev
Pays: United States
ID NLM: 101624857
Informations de publication
Date de publication:
10 Dec 2021
10 Dec 2021
Historique:
received:
30
06
2021
revised:
06
10
2021
accepted:
29
10
2021
entrez:
2
12
2021
pubmed:
3
12
2021
medline:
3
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34853801
doi: 10.1016/j.omtm.2021.10.015
pii: S2329-0501(21)00172-8
pmc: PMC8606349
doi:
Types de publication
Journal Article
Langues
eng
Pagination
551-566Informations de copyright
© 2021 The Authors.
Déclaration de conflit d'intérêts
K.P., D.M.M., and P.M.T. are/have been employees of Sernova Corp., which holds the patent US20190240375A1.
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