Adenovirus-mediated gene transfer results in decreased lysosomal storage in brain and total correction in liver of aspartylglucosaminuria (AGU) mouse.

Aspartylglucosaminuria (AGU) is a lysosomal storage disease leading to mental retardation, which is caused by deficiency of aspartylglucosaminidase (AGA). AGU is strongly enriched in the Finnish population in which one major mutation called AGU(Fin) has been identified. The molecular pathogenesis of AGU as well as the biology of the AGA enzyme have been extensively studied, thus giving a profound basis for therapeutic interventions. In this study we have performed adenovirus-mediated gene transfer to the recently produced mouse model of AGU, which exhibits similar pathophysiology as that in humans. Recombinant adenovirus vectors encoding for the human AGA and AGU(Fin) polypeptides were first applied in primary neurons of AGU mouse to demonstrate wild-type and mutant AGA expression in vitro. In vivo, both of the adenovirus vectors were injected into the tail vein of AGU mice and the expression of AGA was demonstrated in the liver. The adenovirus vectors were also injected intraventricularly into the brain of AGU mice resulting in AGA expression in the ependymal cells lining the ventricles and further, diffusion of AGA into the neighbouring neurons. Also, AGA enzyme injected intraventricularly was shown to transfer across the ependymal cell layer. One month after administration of the wild-type Ad-AGA, a total correction of lysosomal storage in the liver and a partial correction in brain tissue surrounding the ventricles was observed. After administration of the Ad-AGU virus the lysosomal storage vacuoles in liver or brain remained unchanged. These data demonstrate that the lysosomal storage in AGU can be biologically corrected and furthermore, in the brain a limited number of transduced cells can distribute AGA enzyme to the surrounding areas.