title: AAV2 vector harboring a liver-restricted promoter facilitates sustained expression of therapeutic levels of alpha-galactosidase A and the induction of immune tolerance in Fabry mice.
abstract: The successful application of gene therapy for the treatment of genetic diseases such as Fabry is reliant on the development of vectors that are safe and that facilitate sustained expression of therapeutic levels of the transgene product. Here, we report that intravenous administration of a recombinant AAV2 vector encoding human alpha-galactosidase A under the transcriptional control of a liver-restricted enhancer/promoter (AAV2/DC190-alphagal) generated significantly higher levels of expression in BALB/c and Fabry mice than could be realized using the ubiquitous CMV promoter (AAV2/CMVHI-alphagal). Moreover, AAV2/DC190-alphagal-mediated hepatic expression of alpha-galactosidase A was sustained for 12 months in BALB/c mice and was associated with a significantly reduced immune response to the expressed enzyme. Subsequent challenge of the AAV2/DC190-alphagal-treated animals with recombinant human alpha-galactosidase A at 6 months failed to elicit the production of anti-alpha-galactosidase A antibodies, suggesting the induction of immune tolerance in these animals. The levels of expression attained with AAV2/DC190-alphagal in the Fabry mice were sufficient to reduce the abnormal accumulation of globotriaosylceramide in the liver, spleen, and heart to basal levels and in the kidney by approximately 40% at 8 weeks. Together, these results demonstrate that AAV2-mediated gene transfer that limits the expression of alpha-galactosidase A to the liver may be a viable strategy for treating Fabry disease.
authors.affiliation: Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701-9322, USA.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Ziegler
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lonning
authors.forename: Donna
authors.initials: D
authors.lastname: Armentano
authors.forename: Chester
authors.initials: C
authors.lastname: Li
authors.forename: David W
authors.initials: DW
authors.lastname: Souza
authors.forename: Maribeth
authors.initials: M
authors.lastname: Cherry
authors.forename: Christine
authors.initials: C
authors.lastname: Ford
authors.forename: Christine M
authors.initials: CM
authors.lastname: Barbon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Richard
authors.initials: R
authors.lastname: Peluso
authors.forename: Simon
authors.initials: S
authors.lastname: Godwin
authors.forename: Barrie J
authors.initials: BJ
authors.lastname: Carter
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gregory
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Wadsworth
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D004274:DNA, Recombinant / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic / Q000235:genetics; D000795:Fabry Disease / Q000235:genetics / Q000628:therapy*; D005818:Genetic Engineering; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007108:Immune Tolerance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D004274:DNA, Recombinant; D000519:alpha-Galactosidase