1. ¹Department of Neurology and Program in Neuroscience, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
2. ²Department of Biology, Boston College, Chestnut Hill, Massachusetts, USA
3. ³Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands

Correspondence: M Sena-Esteves, Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 13th Street, Room 6309, Charlestown, Massachusetts 02129, USA. E-mail: msesteves@partners.org

Received 11 March 2006; Accepted 24 August 2006.

Abstract

GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by autosomal recessive deficiency of lysosomal acid -galactosidase (gal), 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 gal on enzyme activity and brain GSL content in GM1-gangliosidosis (gal^-/-) mice. Histological analysis of gal distribution in 3-month-old AAV-treated gal^-/- mice showed that enzyme was present at high levels throughout the brain. Biochemical quantification showed that gal 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 gal^-/- mice, were restored to normal levels by AAV treatment. In untreated gal^-/- 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 gal^-/- mice. Therefore we show for the first time that neonatal AAV-mediated gene delivery of lysosomal gal to the brain may be an effective approach for treatment of GM1-gangliosidosis.