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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.
AuthorsM L D Broekman, R C Baek, L A Comer, J L Fernandez, T N Seyfried, M Sena-Esteves
JournalMolecular 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
PMID17164772 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • acid beta-galactosidase
  • beta-Galactosidase
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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