title: Lentivector transduction improves outcomes over transplantation of human HSCs alone in NOD/SCID/Fabry mice.
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.
authors.affiliation: University Health Network, Toronto, Ontario, Canada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Pacienza
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshimitsu
authors.forename: Nobuo
authors.initials: N
authors.lastname: Mizue
authors.forename: Bryan C Y
authors.initials: BC
authors.lastname: Au
authors.forename: James C M
authors.initials: JC
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takenaka
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D002460:Cell Line; D000795:Fabry Disease / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009206:Myocardium / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014161:Transduction, Genetic; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000097:blood / Q000235:genetics*
chemical_list: D018952:Antigens, CD34; D014281:Trihexosylceramides; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C018549:globotriaosylceramide; D000519:alpha-Galactosidase