title: Complete correction of enzymatic deficiency and neurochemistry in the GM1-gangliosidosis mouse brain by neonatal adeno-associated virus-mediated gene delivery.
abstract: GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by autosomal recessive deficiency of lysosomal acid beta-galactosidase (betagal), 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 betagal on enzyme activity and brain GSL content in GM1-gangliosidosis (betagal(-/-)) mice. Histological analysis of betagal distribution in 3-month-old AAV-treated betagal(-/-) mice showed that enzyme was present at high levels throughout the brain. Biochemical quantification showed that betagal 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 betagal(-/-) mice, were restored to normal levels by AAV treatment. In untreated betagal(-/-) 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 betagal(-/-) mice. Therefore we show for the first time that neonatal AAV-mediated gene delivery of lysosomal betagal to the brain may be an effective approach for treatment of GM1-gangliosidosis.
authors.affiliation: Department of Neurology and Program in Neuroscience, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: M L D
authors.initials: ML
authors.lastname: Broekman
authors.forename: R C
authors.initials: RC
authors.lastname: Baek
authors.forename: L A
authors.initials: LA
authors.lastname: Comer
authors.forename: J L
authors.initials: JL
authors.lastname: Fernandez
authors.forename: T N
authors.initials: TN
authors.lastname: Seyfried
authors.forename: M
authors.initials: M
authors.lastname: Sena-Esteves
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002851:Chromatography, High Pressure Liquid; D000229:Dependovirus / Q000235:genetics*; D016537:Gangliosidosis, GM1 / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy; D050356:Lipid Metabolism; D008247:Lysosomes / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D001616:beta-Galactosidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: C021502:acid beta-galactosidase; D001616:beta-Galactosidase