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- Title
Lentivector transduction improves outcomes over transplantation of human HSCs alone in NOD/SCID/Fabry mice.
- Authors
Pacienza, Natalia; Yoshimitsu, Makoto; Mizue, Nobuo; Au, Bryan C Y; Wang, James C M; Fan, Xin; Takenaka, Toshihiro; Medin, Jeffrey A
- Abstract
Fabry disease is a lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A) activity that results in progressive globotriaosylceramide (Gb(3)) deposition. We created a fully congenic nonobese diabetic (NOD)/severe combined immunodeficiency (SCID)/Fabry murine line to facilitate the in vivo assessment of human cell-directed therapies for Fabry disease. This pure line was generated after 11 generations of backcrosses and was found, as expected, to have a reduced immune compartment and background α-gal A activity. Next, we transplanted normal human CD34(+) cells transduced with a control (lentiviral vector-enhanced green fluorescent protein (LV-eGFP)) or a therapeutic bicistronic LV (LV-α-gal A/internal ribosome entry site (IRES)/hCD25). While both experimental groups showed similar engraftment levels, only the therapeutic group displayed a significant increase in plasma α-gal A activity. Gb(3) quantification at 12 weeks revealed metabolic correction in the spleen, lung, and liver for both groups. Importantly, only in the therapeutically-transduced cohort was a significant Gb(3) reduction found in the heart and kidney, key target organs for the amelioration of Fabry disease in humans.
- Publication
Molecular therapy : the journal of the American Society of Gene Therapy, 2012, Vol 20, Issue 7, p1454
- ISSN
1525-0024
- Publication type
Journal Article
- DOI
10.1038/mt.2012.64