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dc.contributor.authorFoust, Kevin D.
dc.contributor.authorFlotte, Terence R.
dc.contributor.authorReier, Paul J.
dc.contributor.authorMandel, Ronald J.
dc.date2022-08-11T08:10:14.000
dc.date.accessioned2022-08-23T17:00:29Z
dc.date.available2022-08-23T17:00:29Z
dc.date.issued2008-01-13
dc.date.submitted2012-01-11
dc.identifier.citationHum Gene Ther. 2008 Jan;19(1):71-82. <a href="http://dx.doi.org/10.1089/hum.2007.104">Link to article on publisher's site</a>
dc.identifier.issn1043-0342 (Linking)
dc.identifier.doi10.1089/hum.2007.104
dc.identifier.pmid18072858
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43807
dc.description.abstractAmyotrophic 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=18072858&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1089/hum.2007.104
dc.subjectAmyotrophic Lateral Sclerosis
dc.subjectAnimals
dc.subjectDNA, Recombinant
dc.subjectDependovirus
dc.subjectEnzyme-Linked Immunosorbent Assay
dc.subjectGene Therapy
dc.subjectGenetic Vectors
dc.subjectGlial Cell Line-Derived Neurotrophic Factor
dc.subjectImmunohistochemistry
dc.subjectMale
dc.subjectPyramidal Tracts
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.subjectSpinal Cord
dc.subjectAllergy and Immunology
dc.subjectGenetics and Genomics
dc.subjectNervous System Diseases
dc.subjectPediatrics
dc.titleRecombinant 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
dc.typeJournal Article
dc.source.journaltitleHuman gene therapy
dc.source.volume19
dc.source.issue1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/peds_pulmonary/22
dc.identifier.contextkey2441383
html.description.abstract<p>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.</p>
dc.identifier.submissionpathpeds_pulmonary/22
dc.contributor.departmentDepartment of Pediatrics
dc.contributor.departmentGene Therapy Center
dc.source.pages71-82


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