1. ¹Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA
2. ²Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital/B114-2000, Charlestown, MA, USA
3. ³Department of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands
4. ⁴Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands

Correspondence: Dr M Sena-Esteves, Department of Neurology, Massachusetts General Hospital Building 149, 13th Street, Room 6309, Charlestown, MA 02129, USA. E-mail: msesteves@partners.org

Received 27 April 2008; Revised 27 August 2008; Accepted 27 August 2008; Published online 25 September 2008.

Abstract

GM1-gangliosidosis is a lysosomal storage disease (LSD) caused by an autosomal recessive deficiency of lysosomal acid -galactosidase (gal). This leads to accumulation of GM1-ganglioside and its asialo derivative GA1 in the central nervous system (CNS), and progressive neurodegeneration. Therapeutic AAV-mediated gene delivery to the brain for LSDs has proven very successful in several animal models. GM1-gangliosidosis is also a prime candidate for AAV-mediated gene therapy in the CNS. As global neuropathology characterizes the most severe forms of this disease, therapeutic interventions need to achieve distribution of gal throughout the entire CNS. Therefore, careful consideration of routes of administration and target structures from where metabolically active enzyme can be produced, released and distributed throughout the CNS, is necessary. The goal of this study was to investigate the pattern and mechanism of distribution of gal in the adult GM1-gangliosidosis mouse brain upon hippocampal injection of an AAV vector-encoding gal. We found evidence that three different mechanisms contribute to its distribution in the brain: (1) diffusion; (2) axonal transport within neurons from the site of production; (3) CSF flow in the perivascular space of Virchow–Robin. In addition, we found evidence of axonal transport of vector-encoded mRNA.