Complete Correction of Enzymatic Deficiency and Neurochemistry in the GM1-gangliosidosis Mouse Brain by Neonatal Adeno-associated Virus–mediated Gene Delivery

GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by autosomal recessive deficiency of lysosomal acid β-galactosidase (βgal), and characterized by accumulation of GM1-ganglioside and GA1 in the brain. Here we examined the effect of neonatal intracerebroventricular (i.c.v.) injection of an adeno-associated virus (AAV) vector encoding mouse βgal on enzyme activity and brain GSL content in GM1-gangliosidosis (βgal−/−) mice. Histological analysis of βgal distribution in 3-month-old AAV-treated βgal−/− mice showed that enzyme was present at high levels throughout the brain. Biochemical quantification showed that βgal activity in AAV-treated brains was 7- to 65-fold higher than in wild-type controls and that brain GSL levels were normalized. Cerebrosides and sulfatides, which were reduced in untreated βgal−/− mice, were restored to normal levels by AAV treatment. In untreated βgal−/− brains, cholesterol was present at normal levels but showed abnormal cellular distribution consistent with endosomal/lysosomal localization. This feature was also corrected in AAV-treated mice. The biochemical and histological parameters analyzed in this study showed that normal brain neurochemistry was achieved in AAV-treated βgal−/− mice. Therefore we show for the first time that neonatal AAV-mediated gene delivery of lysosomal βgal to the brain may be an effective approach for treatment of GM1-gangliosidosis.