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.
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Authors | M L D Broekman, R C Baek, L A Comer, J L Fernandez, T N Seyfried, M Sena-Esteves |
Journal | Molecular therapy : the journal of the American Society of Gene Therapy
(Mol Ther)
Vol. 15
Issue 1
Pg. 30-7
(Jan 2007)
ISSN: 1525-0024 [Electronic] United States |
PMID | 17164772
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- acid beta-galactosidase
- beta-Galactosidase
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Topics |
- Animals
- Animals, Newborn
- Chromatography, High Pressure Liquid
- Dependovirus
(genetics)
- Gangliosidosis, GM1
(enzymology, genetics, pathology, therapy)
- Genetic Therapy
- Lipid Metabolism
- Lysosomes
(enzymology)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- beta-Galactosidase
(deficiency, genetics, metabolism)
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