title: Partial correction of the alpha-galactosidase A deficiency and reduction of glycolipid storage in Fabry mice using synthetic vectors.
abstract: BACKGROUND
  Fabry disease is a recessive, X-linked disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, leading to an accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in most tissues of the body. The goal of this study was to determine if systemic delivery of a nonviral vector could correct the enzyme deficiency and reduce the levels of GL-3 in different tissues of a transgenic knockout mouse model of the disease.
  
  
  METHODS
  Cationic lipid was complexed with a CpG-depleted plasmid DNA vector and then injected intravenously into Fabry mice. The levels of alpha-galactosidase A and GL-3 in different tissues were assayed at various time points after injection.
  
  
  RESULTS
  Expression of alpha-galactosidase A was detected in the different tissues of Fabry mice for up to 3 months after complex administration, but resulted in minimal reductions in GL-3 levels. However, the use of the anti-inflammatory drug dexamethasone and multiple dosing increased alpha-galactosidase A expression and resulted in significant reductions of GL-3 in all the organs with the exception of the kidney. In addition, injecting complex into young Fabry mice partially prevented the normal accumulation of GL-3 in the heart, lung, and liver.
  
  
  CONCLUSIONS
  Systemic delivery of a cationic lipid-pDNA complex partially corrected the enzyme deficiency and reduced glycolipid storage in a mouse model of Fabry disease. The results are one of the few demonstrations of long-term efficacy in a genetic disease model using nonviral vectors. However, substantial improvements in expression, especially in critical organs such as the kidney, are required before these vectors can become a viable approach to treat Fabry disease and other lysosomal storage disorders.
authors.affiliation: Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701-9322, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Przybylska
authors.forename: I-Huan
authors.initials: IH
authors.lastname: Wu
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhao
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Ziegler
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Tousignant
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Scheule
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Nelson S
authors.initials: NS
authors.lastname: Yew
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000235:genetics* / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D008055:Lipids; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000235:genetics; D014281:Trihexosylceramides / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D008055:Lipids; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase