Improved efficacy of gene therapy approaches for Pompe disease using a new, immune-deficient GSD-II mouse model

Gene Therapy
Fang XuAndrea Amalfitano

Abstract

Glycogen storage disease type II (GSD-II) is a lysosomal storage disorder in which the lack of human acid-alpha glucosidase (hGAA) activity results in massive accumulations of glycogen in cardiac and skeletal muscle fibers. Affected individuals die of cardiorespiratory failure secondary to the skeletal and/or cardiac muscle involvement. Recombinant hGAA enzyme replacement therapy (ERT) is currently in clinical trials and, although promising, ERT may be limited by large-scale production issues and/or the need for frequent infusions. These limitations could be circumvented or augmented by gene therapy strategies. Previous findings in our lab demonstrated that hepatic targeting of a modified adenovirus vector expressing human GAA was able to correct the glycogen accumulation in multiple affected muscles in the GAA-KO mice, by virtue of high-level, hepatic secretion of hGAA. However, although the vector persisted and expressed hGAA for 6 months in the liver, plasma hGAA was not detectable beyond 10 dpi (days postinjection), and reaccumulation of glycogen was observed. Two possibilities may have contributed to this phenomenon, the shut down of the CMV promoter and/or the onset of high levels of anti-hGAA antibodies. In order to test...Continue Reading

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Citations

Nov 21, 2008·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Benedikt SchoserNina Raben
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