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 aspartylglucosam inidase (AGA). AGU is strongly enriched in the Finnish population in w hich one major mutation called AGU(Fin) has been identified. The mol; ecular pathogenesis of AGU as well as the biology of the AGA enzyme ha ve been extensively studied, thus giving a profound basis for therapeu tic interventions. In this study we have performed adenovirus-mediated gene transfer to the recently produced mouse model of AGU, which exhi bits similar pathophysiology as that in humans. Recombinant adenovirus vectors encoding for the human AGA and AGU(Fin) polypeptides were fir st applied in primary neurons of AGU mouse to demonstrate wild-type an d mutant AGA expression in vitro. In vivo, both of the adenovirus vect ors were injected into the tail vein of AGU mice and the expression of AGA was demonstrated in the liver. The adenovirus vectors were also i njected 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 inje cted intraventricularly was shown to transfer across the ependymal cel l layer. One month after administration of the wild-type Ad-AGA, a tot al correction of lysosomal storage in the fiver and a partial correcti on in brain tissue surrounding the ventricles was observed After admin istration 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 t o the transduced cells can surrounding areas.