Use of nonviral promoters in adenovirus-mediated gene therapy: reduction of lysosomal storage in the aspartylglucosaminuria mouse

The Journal of Gene Medicine
Salli VirtaMinna Laine

Abstract

Aspartylglucosaminuria (AGU) is a lysosomal storage disease with severe neurodegenerative clinical features resulting from the deficiency of lysosomal aspartylglucosaminidase (AGA). The AGU knockout mouse is a good model to test different therapy strategies, as it mimics well the human pathogenesis of the disease exhibiting storage vacuoles in all tissues. In this study we investigated the efficiency of nonviral promoters in adenovirus-mediated gene therapy. The deficient corrective enzyme, AGA, was expressed using two tissue-specific promoters, neuron-specific enolase (NSE), astrocyte-specific (GFAP) and the endogenous AGA promoter. An intrastriatal injection site was chosen due to its wide connections in the central nervous system (CNS). The expression of AGA was analyzed 1 week, 2 weeks, 4 weeks, 2 months and 4 months after the virus injection by lysosomal AGA-specific immunostaining. A correction of the lysosomal storage in the brain of treated mice was also studied using toluidine blue stained thin sections. The overexpressed AGA enzyme was detected in addition to the injection site, also in the ipsilateral parietal cortex indicating migration of AGA in the brain tissue. Duration of AGA expression was markedly longer with ...Continue Reading

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Citations

Jun 1, 2015·Journal of Neuroradiology. Journal De Neuroradiologie·Anna M TokolaTaina H Autti
Oct 28, 2019·AJNR. American Journal of Neuroradiology·A TokolaT Autti
Jan 14, 2021·Journal of Child Neurology·Kimberly GoodspeedTroy C Lund

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