title: Demonstration of feasibility of in vivo gene therapy for Gaucher disease using a chemically induced mouse model.
abstract: Progress towards developing gene therapy for Gaucher disease has been hindered by the lack of an animal model. Here we describe a mouse model of Gaucher disease which has a chemically induced deficiency of glucocerebrosidase and that accumulates elevated levels of glucosylceramide (GL-1) in the lysosomes of Kupffer cells. Administration of mannose-terminated glucocerebrosidase (Cerezyme) resulted in the reduction of GL-1 levels in the livers of these animals. Gene transduction of hepatocytes with a plasmid DNA vector encoding human glucocerebrosidase (pGZB-GC) generated high-level expression and secretion of the enzyme into systemic circulation with consequent normalization of Kupffer cell GL-1 levels. This suggested that the de novo synthesized and unmodified enzyme produced by hepatocyte transduction was also capable of being delivered to the cells that are primarily affected in Gaucher disease. Immunolocalization studies also revealed that preferential transduction and expression of human glucocerebrosidase in the Kupffer cells with subsequent reduction in the GL-1 levels could be attained with a low dose of a recombinant adenoviral vector encoding the human enzyme (Ad2/CMV-GC). This observation raises the possibility of gene therapy for Gaucher disease that involves directly transducing the affected histiocytes using recombinant adenoviral vectors. Together, these data demonstrate the potential for use of in vivo gene therapy vectors for treating Gaucher disease.
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts, 01701-9322, USA. john.marshall@genzyme.com
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: Kerry Anne
authors.initials: KA
authors.lastname: McEachern
authors.forename: Julie A Cavanagh
authors.initials: JA
authors.lastname: Kyros
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Nietupski
authors.forename: Tracey
authors.initials: T
authors.lastname: Budzinski
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Ziegler
authors.forename: Nelson S
authors.initials: NS
authors.lastname: Yew
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sullivan
authors.forename: Abraham
authors.initials: A
authors.lastname: Scaria
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: John A
authors.initials: JA
authors.lastname: Barranger
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005776:Gaucher Disease / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D005963:Glucosylceramides / Q000378:metabolism; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D005963:Glucosylceramides; D005962:Glucosylceramidase; C090568:imiglucerase