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Mechanisms of distribution of mouse β-galactosidase in the adult GM1-gangliosidosis brain

Gene Therapy volume 16, pages 303–308 (2009)Cite this article

Abstract

GM1-gangliosidosis is a lysosomal storage disease (LSD) caused by an autosomal recessive deficiency of lysosomal acid β-galactosidase (βgal). 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 βgal 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 βgal in the adult GM1-gangliosidosis mouse brain upon hippocampal injection of an AAV vector-encoding βgal. 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.

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Acknowledgements

This work was supported by NIH Grant R21NS053993. We thank Deidre McCarthy for her help with laser capture microdissection, and the Massachusetts General Hospital Neuroscience Center Microscopy and Image Analysis Core (NIH Grant P30NS045776) for use of the laser capture microdissection system and Nikon Supercoolscan 9000 slide scanner.

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Authors and Affiliations

  1. Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA

    M L D Broekman, L A Tierney & M Sena-Esteves

  2. Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital/B114-2000, Charlestown, MA, USA

    C Benn, P Chawla & J H Cha

  3. Department of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands

    M L D Broekman

  4. Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands

    M L D Broekman

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  1. M L D Broekman
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  2. L A Tierney
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  3. C Benn
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  4. P Chawla
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  5. J H Cha
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  6. M Sena-Esteves
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Correspondence to M Sena-Esteves.

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Broekman, M., Tierney, L., Benn, C. et al. Mechanisms of distribution of mouse β-galactosidase in the adult GM1-gangliosidosis brain. Gene Ther 16, 303–308 (2009). https://doi.org/10.1038/gt.2008.149

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