- 作者: Jin-Ok Choi; Mi Hee Lee; Hae-Young Park; Sung-Chul Jung
- 作者服務機構: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea
- 中文摘要: --
- 英文摘要:
Background : 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) vectormediated
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 18-week-old male Fabry mice through the tail vein. The α-
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 α-Gal A enzyme activity. Enzyme activity was elevated for
up to 60 weeks. In addition, expression of the α-Gal A protein was identified in the
presence of rAAV2/8-hAGA at 6, 12, and 24 weeks after treatment. α-Gal A activity
was significantly higher in the mice treated with rAAV2/8-hAGA than in Fabry mice
that received ERT. Along with higher α-Gal A activity in the kidney of the Fabry
mice treated with gene therapy, immunohistochemical studies showed more α-Gal A
expression in the proximal tubules and glomerulus, and less Gb3 deposition in Fabry mice treated with this gene therapy than in mice given ERT. The α-gal A gene
transfer significantly reduced the accumulation of Gb3 in the tubules and podocytes of
the kidney. Electron microscopic analysis of the kidneys of Fabry mice also showed
that gene therapy was more effective than ERT.
Conclusions :
The rAAV2/8-hAGA mediated α-Gal A gene therapy provided improved efficiency
over ERT in the Fabry disease mouse model. Furthermore, rAAV2/8-hAGA-mediated
expression showed a greater effect in the kidney than ERT. - 中文關鍵字: --
- 英文關鍵字: --