Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A.
ET3
FVIII
HSQ
cell therapy
codon-optimization
gene therapy
hemophilia A
placental cells
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:
12 Jun 2020
12 Jun 2020
Historique:
received:
19
02
2020
accepted:
09
03
2020
entrez:
8
4
2020
pubmed:
8
4
2020
medline:
8
4
2020
Statut:
epublish
Résumé
The delivery of factor VIII (FVIII) through gene and/or cellular platforms has emerged as a promising hemophilia A treatment. Herein, we investigated the suitability of human placental cells (PLCs) as delivery vehicles for FVIII and determined an optimal FVIII transgene to produce/secrete therapeutic FVIII levels from these cells. Using three PLC cell banks we demonstrated that PLCs constitutively secreted low levels of FVIII, suggesting their suitability as a transgenic FVIII production platform. Furthermore, PLCs significantly increased FVIII secretion after transduction with a lentiviral vector (LV) encoding a myeloid codon-optimized bioengineered FVIII containing high-expression elements from porcine FVIII. Importantly, transduced PLCs did not upregulate cellular stress or innate immunity molecules, demonstrating that after transduction and FVIII production/secretion, PLCs retained low immunogenicity and cell stress. When LV encoding five different bioengineered FVIII transgenes were compared for transduction efficiency, FVIII production, and secretion, data showed that PLCs transduced with LV encoding hybrid human/porcine FVIII transgenes secreted substantially higher levels of FVIII than did LV encoding B domain-deleted human FVIII. In addition, data showed that in PLCs, myeloid codon optimization is needed to increase FVIII secretion to therapeutic levels. These studies have identified an optimal combination of FVIII transgene and cell source to achieve clinically meaningful levels of secreted FVIII.
Identifiants
pubmed: 32258210
doi: 10.1016/j.omtm.2020.03.001
pii: S2329-0501(20)30031-0
pmc: PMC7109377
doi:
Types de publication
Journal Article
Langues
eng
Pagination
465-477Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL130856
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL135853
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL148681
Pays : United States
Informations de copyright
© 2020 The Author(s).
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