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    Recombinant adeno-associated virus-mediated global anterograde delivery of glial cell line-derived neurotrophic factor to the spinal cord: comparison of rubrospinal and corticospinal tracts in the rat

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    Authors
    Foust, Kevin D.
    Flotte, Terence R.
    Reier, Paul J.
    Mandel, Ronald J.
    UMass Chan Affiliations
    Department of Pediatrics
    Gene Therapy Center
    Document Type
    Journal Article
    Publication Date
    2008-01-13
    Keywords
    Amyotrophic Lateral Sclerosis
    Animals
    DNA, Recombinant
    Dependovirus
    Enzyme-Linked Immunosorbent Assay
    Gene Therapy
    Genetic Vectors
    Glial Cell Line-Derived Neurotrophic Factor
    Immunohistochemistry
    Male
    Pyramidal Tracts
    Rats
    Rats, Sprague-Dawley
    Spinal Cord
    Allergy and Immunology
    Genetics and Genomics
    Nervous System Diseases
    Pediatrics
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    Link to Full Text
    http://dx.doi.org/10.1089/hum.2007.104
    Abstract
    Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of spinal lower motoneurons. Gene delivery is a promising strategy to deliver therapeutic molecules to these vulnerable cells. However, definition of an optimal route of delivery capable of accessing neurons over a considerable extent of the neuraxis represents a significant logistical problem. Intramuscular vector injections are not ideal as this approach would involve hundreds of injections to completely treat an ALS patient and also would be dependent on retrograde transport of the viral platform of choice. Alternatively, upper motoneurons could deliver trophic factors over considerable distances by anterograde transport after a relatively localized intracerebral injection. To test this approach, the present study was designed to compare the corticospinal (CST) and rubrospinal (RST) tracts for their ability to transport recombinant adeno-associated virus serotype 5 (rAAV5)-derived green fluorescent protein (GFP) or glial cell line-derived neurotrophic factor (GDNF) to the spinal cord. Unilateral injections of rAAV5-GFP into the red nucleus (RN) or motor cortex of normal rats produced GFP-positive fibers in the appropriate descending tracts extending to the lumbar spinal cord. For both tracts, GFP-positive axonal projections into the spinal gray matter were consistently observed. GDNF immunohistochemistry demonstrated that confirmed RN injections resulted in GDNF-positive fibers projecting into spinal gray matter as seen in the GFP group. In contrast, confirmed cortical rAAV5-GDNF injections resulted in less evident staining in spinal cord. Spinal cord GDNF levels were elevated at distances up to 72 mm from the injection sites, and confirmed that RST-related GDNF transport to spinal cord surpassed CST-associated delivery.
    Source
    Hum Gene Ther. 2008 Jan;19(1):71-82. Link to article on publisher's site
    DOI
    10.1089/hum.2007.104
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/43807
    PubMed ID
    18072858
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1089/hum.2007.104
    Scopus Count
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