TAILIEUCHUNG - Characterization of Fabry mice treated with recombinant adeno-associated virus 2/8-mediated gene transfer

Enzyme replacement therapy (ERT) with α-galactosidase A (α-Gal A) is currently the most effective therapeutic strategy for patients with Fabry disease, a lysosomal storage disease. However, ERT has limitations of a short half-life, requirement for frequent administration, and limited efficacy for patients with renal failure. Therefore, we investigated the efficacy of recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for a Fabry disease mouse model and compared it with that of ERT. Methods: A pseudotyped rAAV2/8 vector encoding α-Gal A cDNA (rAAV2/8-hAGA) was prepared and injected into 18week-old male Fabry mice through the tail vein. The α-Gal A. | Choi et al. Journal of Biomedical Science 2010 17 26 http content 17 1 26 a NSC Tha cost of publication In Journal of Blomodlcal Science Is boms by tlM National Science Council Taiwan JOURNAL OF BIOMEDICAL SCIENCE RESEARCH Open Access Characterization of Fabry mice treated with recombinant adeno-associated virus 2 8-mediated gene transfer Jin-Ok Choi Mi Hee Lee Hae-Young Park and Sung-Chul Jung Abstract Background Enzyme replacement therapy ERT with a-galactosidase A a-Gal A is currently the most effective therapeutic strategy for patients with Fabry disease a lysosomal storage disease. However ERT has limitations of a short half-life requirement for frequent administration and limited efficacy for patients with renal failure. Therefore we investigated the efficacy of recombinant adeno-associated virus rAAV vector-mediated gene therapy for a Fabry disease mouse model and compared it with that of ERT. Methods A pseudotyped rAAV2 8 vector encoding a-Gal A cDNA rAAV2 8-hAGA was prepared and injected into 18-week-old male Fabry mice through the tail vein. The a-Gal A expression level and globotriaosylceramide Gb3 levels in the Fabry mice were examined and compared with Fabry mice with ERT. Immunohistochemical and ultrastructural studies were conducted. Results Treatment of Fabry mice with rAAV2 8-hAGA resulted in the clearance of accumulated Gb3 in tissues such as liver spleen kidney heart and brain with concomitant elevation of a-Gal A enzyme activity. Enzyme activity was elevated for up to 60 weeks. In addition expression of the a-Gal A protein was identified in the presence of rAAV2 8-hAGA at 6 12 and 24 weeks after treatment. a-Gal A activity was significantly higher in the mice treated with rAAV2 8-hAGA than in Fabry mice that received ERT. Along with higher a-Gal A activity in the kidney of the Fabry mice treated with gene therapy immunohistochemical studies showed more a-Gal A expression in the proximal tubules and glomerulus and less Gb3 .

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