Olgasi, C, Borsotti, C, Merlin, S, Bergmann, T, Bittorf, P, Adewoye, AB, Wragg, NM, Patterson, K, Calabria, A, Benedicenti, F, Cucci, A, Borchiellini, A, Pollio, B, Montini, E, Mazzuca, DM, Zierau, M, Stolzing, A, Toleikis, PM, Braspenning, J and Follenzi, A (2021) Efficient and safe correction of hemophilia A by lentiviral vector-transduced BOECs in an implantable device. Molecular Therapy - Methods & Clinical Development, 23. pp. 551-566. ISSN 2329-0501

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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 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 pre-clinical 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.

Item Type: Article
Additional Information: The final version of this article and all relevant information related to it, including copyrights, can be found online via the publisher website at; https://www.sciencedirect.com/science/article/pii/S2329050121001728 © 2021 Elsevier B.V. or its licensors or contributors. ScienceDirect ® is a registered trademark of Elsevier B.V.
Subjects: R Medicine > R Medicine (General)
R Medicine > RA Public aspects of medicine
R Medicine > RC Internal medicine
T Technology > T Technology (General)
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Depositing User: Symplectic
Date Deposited: 09 Nov 2021 16:05
Last Modified: 13 Apr 2022 12:57
URI: https://eprints.keele.ac.uk/id/eprint/10251

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