Long-term persistence of human bone marrow stromal cells transduced with factor VIII-retroviral vectors and transient production of therapeutic factor levels of human factor VIII in non-myeloblated immunodeficient mice

Chuah, Marinee K.L.;Van Damme, An;Zwinnen, Hans;Goovaerts, Inge;Vandendriessche, Thierry;et.al.
(2004) Human Gene Therapy — Vol. 11, p. 729-738 (2004)

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  • Chuah, Marinee K.L.
    Author
  • Van Damme, Anorcid-logoUCLouvain
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  • Zwinnen, Hans
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  • Goovaerts, Inge
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  • Vandendriessche, Thierry
    Collaborator
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Abstract
(en) The potential of using bone marrow (BM)-derived human stromal cells for ex vivo gene therapy of hemophilia A was evaluated. BM stromal cells were transduced with an intron-based Moloney murine leukemia virus (Mo-MuLV) retroviral vector that contained the B domain-deleted human factor VIII (FVIII Delta B) cDNA. This FVIII-retroviral vector was pseudotyped with the gibbon ape leukemia virus envelope (GALV-env) to attain higher transduction efficiencies. Using optimized transduction methods, high in vitro FVIII expression levels of 700 to 2500 mU of FVIII/106 cells per 24 hr were achieved without selective enrichment of the transduced BM stromal cells. After xenografting of 1.5-3 X 106 engineered BM stromal cells into the spleen of nonobese diabetic severe combined immunodeficient (NOD-SCID) mice, human plasma FVIII levels rose to 13 +/- 4 ng/ml but declined to basal levels by 3 weeks postinjection because of promoter inactivation. About 10% of these stromal cells engrafted in the spleen and persisted for at least 4 months after transplantation in the absence of myeloablative conditioning. No human BM stromal cells could be detected in other organs. These findings indicate that retroviral vector-mediated gene therapy using engineered BM stromal cells may lead to therapeutic levels of FVIII in vivo and that long-term engraftment of human BM stromal cells was achieved in the absence of myeloablative conditioning and without neo-organs. Hence, BM stromal cells may be useful for gene therapy of hemophilia A, provided prolonged expression can be achieved by using alternative promoters.
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Chuah, M. K. L. (2004). Long-term persistence of human bone marrow stromal cells transduced with factor VIII-retroviral vectors and transient production of therapeutic factor levels of human factor VIII in non-myeloblated immunodeficient mice. Human Gene Therapy, 11, 729-738. https://doi.org/10.1089/10430340050015626 (Original work published 2004)