title: Alpha-galactosidase A-Tat fusion enhances storage reduction in hearts and kidneys of Fabry mice.
abstract: The protein transduction domain from human immunodeficiency virus (HIV) Tat allows proteins to penetrate the cell membrane. Enhanced cellular uptake of therapeutic proteins could benefit a number of disorders. This is especially true for lysosomal storage disorders (LSDs) where enzyme replacement therapy (ERT) and gene therapy have been developed. We developed a novel recombinant lentiviral vector (LV) that engineers expression of alpha-galactosidase A (alpha-gal A)-Tat fusion protein for correction of Fabry disease, the second-most prevalent LSD with manifestations in the brain, kidney and heart. In vitro experiments confirmed mannose-6-phosphate independent uptake of the fusion factor. Next, concentrated therapeutic LV was injected into neonatal Fabry mice. Analysis of tissues at 26 wks demonstrated similar alpha-gal A enzyme activities but enhanced globotriaosylceramide (Gb3) reduction in hearts and kidneys compared with the alpha-gal A LV control. This strategy might advance not only gene therapy for Fabry disease and other LSDs, but also ERT, especially for cardiac Fabry disease.
authors.affiliation: University Health Network (UHN), Toronto, Ontario, Canada.
authors.forename: Koji
authors.initials: K
authors.lastname: Higuchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshimitsu
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Guo
authors.forename: Vanessa I
authors.initials: VI
authors.lastname: Rasaiah
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yen
authors.forename: Chuwa
authors.initials: C
authors.lastname: Tei
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takenaka
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy / Q000379:methods*; D000795:Fabry Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D015756:Genes, tat; D015316:Genetic Therapy / Q000379:methods*; D006678:HIV / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase
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