Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors
- Andrew I. Brooks*,†,‡,
- Colleen S. Stein§,
- Stephanie M. Hughes§,
- Jason Heth¶,
- Paul M. McCray, Jr.‖,
- Sybille L. Sauter**,
- Julie C. Johnston**,
- Deborah A. Cory-Slechta*,†,
- Howard J. Federoff†,‡,‡‡, and
- Beverly L. Davidson§,‡‡,††,§§
- Departments of §Internal Medicine, ††Neurology, §§Physiology and Biophysics, ¶Neurosurgery, and ‖Pediatrics, University of Iowa Program in Gene Therapy, University of Iowa College of Medicine, Iowa City, IA 52242; *Department of Environmental Medicine, †Centers for Functional Genomics, and ‡Aging and Developmental Biology, University of Rochester Medical Center, Rochester, NY 14642; and **Chiron Technologies, Center for Gene Therapy, San Diego, CA 92121
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Edited by Roscoe O. Brady, National Institutes of Health, Bethesda, MD, and approved February 20, 2002 (received for review January 8, 2002)
Abstract
Gene transfer vectors based on lentiviruses can transduce terminally differentiated cells in the brain; however, their ability to reverse established behavioral deficits in animal models of neurodegeneration has not previously been tested. When recombinant feline immunodeficiency virus (FIV)-based vectors expressing β-glucuronidase were unilaterally injected into the striatum of adult β-glucuronidase deficient [mucopolysaccharidosis type VII (MPS VII)] mice, an animal model of lysosomal storage disease, there was bihemispheric correction of the characteristic cellular pathology. Moreover, after the injection of FIV-based vectors expressing β-glucuronidase into brains of β-glucuronidase-deficient mice with established impairments in spatial learning and memory, there was dramatic recovery of behavioral function. Cognitive improvement resulting from expression of β-glucuronidase was associated with alteration in expression of genes associated with neuronal plasticity. These data suggest that enzyme replacement to the MPS VII central nervous system goes beyond restoration of β-glucuronidase activity in the lysosome, and imparts improvements in plasticity and spatial learning.
Footnotes
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↵ ‡‡ To whom reprint requests may be addressed. E-mail: beverly-davidson{at}uiowa.edu or howard_federoff{at}urmc.rochester.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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See commentary on page 5760.
- Abbreviations:
- MPS VII,
- Mucopolysaccharidoses type VII;
- FIV,
- feline immunodeficiency virus;
- LSD,
- lysosomal storage disease;
- CNS,
- central nervous system;
- TU,
- transducing units;
- CMV,
- cytomegalovirus;
- RAPC,
- repeated acquisition and performance chamber;
- RA,
- repeated acquisition;
- P,
- performance;
- QPCR,
- quantitative real time PCR;
- MCS,
- multiple cloning site;
- RSV,
- Rous sarcoma virus
- Copyright © 2002, The National Academy of Sciences
