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The Journal of Neuroscience, April 15, 2003, 23(8):3302

Intravitreal Gene Therapy Reduces Lysosomal Storage in Specific Areas of the CNS in Mucopolysaccharidosis VII Mice

Anne K. Hennig¹, Beth Levy⁴, Judith Mosinger Ogilvie^{2, 5}, Carole A. Vogler⁴, Nancy Galvin⁴, Steven Bassnett², and Mark S. Sands^{1, 3}

¹ Department of Internal Medicine, Division of Stem Cell Biology, and Departments of ² Ophthalmology and Visual Sciences and ³ Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, ⁴ Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri 63107, and ⁵ Fay and Carl Simons Center for the Biology of Hearing and Deafness, Central Institute for the Deaf, St. Louis, Missouri 63110

The mucopolysaccharidoses (MPSs) are lysosomal storage diseases resulting from impaired catabolism of sulfated glycosaminoglycans. MPS VII mice lack lysosomal -glucuronidase (GUSB) activity, leading to the accumulation of partially degraded chondroitin, dermatan, and heparan sulfates in most tissues. Consequently, these mice develop most of the symptoms exhibited by human MPS VII patients, including progressive visual and cognitive deficits. To investigate the effects of reducing lysosomal storage in nervous tissues, we injected recombinant adeno-associated virus encoding GUSB directly into the vitreous humor of young adult mice. Interestingly, GUSB activity was subsequently detected in the brains of the recipients. At 8-12 weeks after treatment, increased GUSB activity and reduced lysosomal distension were found in regions of the thalamus and tectum that received inputs from the injected eye. Lysosomal storage was also reduced in adjacent nonvisual regions, including the hippocampus, as well as in the visual cortex. The findings suggest that both diffusion and trans-synaptic transfer contribute to the dissemination of enzyme activity within the CNS. Intravitreal injection may thus provide a means of delivering certain therapeutic gene products to specific areas within the CNS.

Key words: CNS; gene therapy; genetic diseases; inborn errors of metabolism; axonal transport; lysosomal storage reduction

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2383302-06$05.00/0

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