title: Enzymatic corrections for cells derived from Fabry disease patients by a recombinant adenovirus vector.
abstract: Fabry disease is an X-linked inherited metabolic disorder caused by a deficiency of alpha-galactosidase (alpha-gal), resulting in the accumulation of ceramide trihexoside (CTH) in body fluids and in many organs and tissues. We constructed a recombinant adenovirus with a human alpha-gal cDNA (AxCAG alpha-gal), and transfected this vector to skin fibroblasts from Fabry patients. Transfected cells expressed high amounts of alpha-gal in their cytoplasm, and a high level of alpha-gal activity was detected in the medium. The accumulated CTH in the fibroblasts disappeared 3 days after infection. The secreted alpha-gal also eliminated the accumulated CTH from uninfected patient's cells. The enzyme may be taken up through mannose-6-phosphate receptors, as the addition of mannose-6-phosphate to the medium completely inhibited the uptake of the enzyme. The infected cells continued to express alpha-gal for more than 10 days. These results suggest that AxCAG alpha-gal could be used as enzyme replacement gene therapy for Fabry disease.
authors.affiliation: Department of Inherited Metabolic Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. sakuraga@ncnp.gp.jp
authors.forename: K
authors.initials: K
authors.lastname: Ohsugi
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Itoh
authors.forename: H
authors.initials: H
authors.lastname: Sakuraba
authors.forename: N
authors.initials: N
authors.lastname: Sakuragawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D004274:DNA, Recombinant / Q000138:chemical synthesis / Q000627:therapeutic use*; D000795:Fabry Disease / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D012867:Skin / Q000166:cytology; D014162:Transfection; D000519:alpha-Galactosidase / Q000096:biosynthesis / Q000235:genetics / Q000493:pharmacokinetics*
chemical_list: D004274:DNA, Recombinant; D000519:alpha-Galactosidase