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
| Autor: | Maribeth Cherry, Christine M. Barbon, Seng H. Cheng, Christine Ford, Robin J. Ziegler, Guangping Gao, Donna Armentano, David W. Souza, Robert J. Desnick, James M. Wilson, Barrie J. Carter, Chester Li, Scott Lonning, Simon Godwin, Richard J. Gregory, Samuel C. Wadsworth, Richard W. Peluso |
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| Rok vydání: | 2003 |
| Předmět: |
Male
viruses Genetic enhancement Transgene Genetic Vectors Globotriaosylceramide DNA Recombinant Mice Transgenic Immune tolerance chemistry.chemical_compound Mice Immune system Drug Discovery medicine Genetics Immune Tolerance Animals Vector (molecular biology) Promoter Regions Genetic Molecular Biology Pharmacology Mice Inbred BALB C biology Genetic Therapy Dependovirus medicine.disease Fabry disease Molecular biology Disease Models Animal Enhancer Elements Genetic chemistry Liver alpha-Galactosidase biology.protein Molecular Medicine Fabry Disease Antibody Genetic Engineering |
| Zdroj: | Molecular therapy : the journal of the American Society of Gene Therapy. 9(2) |
| ISSN: | 1525-0016 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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