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The Journal of Neuroscience, October 12, 2005, 25(41):9321-9327; doi:10.1523/JNEUROSCI.2936-05.2005

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Neurobiology of Disease
Functional Correction of CNS Phenotypes in a Lysosomal Storage Disease Model Using Adeno-Associated Virus Type 4 Vectors

Gumei Liu,¹ Inês Martins,¹ John A. Wemmie,⁴ John A. Chiorini,⁵ and Beverly L. Davidson^1,2,3

Program in Gene Therapy, Departments of ¹Internal Medicine, ²Neurology, ³Physiology and Biophysics, and ⁴Psychiatry, University of Iowa, Iowa City, Iowa 52242, and ⁵The National Institutes of Health, Bethesda, Maryland 20892

Lysosomal storage diseases (LSDs) represent a significant portion of inborn metabolic disorders. More than 60% of LSDs have CNS involvement. LSD therapies for systemic diseases have been developed, but efficacy does not extend to the CNS. In this study, we tested whether adeno-associated virus type 4 (AAV4) vectors could mediate global functional and pathological improvements in a murine model of mucopolysaccharidosis type VII (MPS VII) caused by -glucuronidase deficiency. Recombinant AAV4 vectors encoding -glucuronidase were injected unilaterally into the lateral ventricle of MPS VII mice with established disease. Transduced ependyma expressed high levels of recombinant enzyme, with secreted enzyme penetrating cerebral and cerebellar structures, as well as the brainstem. Immunohistochemical studies revealed close association of recombinant enzyme and brain microvasculature, indicating that -glucuronidase reached brain parenchyma via the perivascular spaces lining blood vessels. Aversive associative learning was tested by context fear conditioning. Compared with age-matched heterozygous controls, affected mice showed impaired conditioned fear response and context discrimination. This behavioral deficit was reversed 6 weeks after gene transfer in AAV4 -glucuronidase-treated MPS VII mice. Our data show that ependymal cells can serve as a source of enzyme secretion into the surrounding brain parenchyma and CSF. Secreted enzymes subsequently spread via various routes to reach structures throughout the brain and mediated pathological and functional disease correction. Together, our proof-of-principal experiments suggest a unique and efficient manner for treating the global CNS deficits in LSD patients.

Key words: lysosomal storage disease; mucopolysaccharidoses; -glucuronidase; AAV4; CSF; perivascular; fear conditioning

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Received May 16, 2005; revised August 23, 2005; accepted August 25, 2005.

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