Immunogenicity of intrathecal plasmid gene delivery: cytokine release and effects on transgene expression
Background One method for the delivery of therapeutic proteins to the spinal cord is to inject nonviral gene vectors including plasmid DNA into the cerebrospinal fluid (CSF) that surrounds the spinal cord (intrathecal space). This approach has produced therapeutic benefits in animal models of diseas...
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Published in | The journal of gene medicine Vol. 11; no. 9; pp. 782 - 790 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Chichester, UK
John Wiley & Sons, Ltd
01.09.2009
Wiley Periodicals Inc |
Subjects | |
Online Access | Get full text |
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Summary: | Background
One method for the delivery of therapeutic proteins to the spinal cord is to inject nonviral gene vectors including plasmid DNA into the cerebrospinal fluid (CSF) that surrounds the spinal cord (intrathecal space). This approach has produced therapeutic benefits in animal models of disease and several months of protein expression; however, there is little information available on the immune response to these treatments in the intrathecal space, the relevance of plasmid CpG sequences to any plasmid‐induced immune response, or the effect of this immune response on transgene expression.
Methods
In the present study, coding or noncoding plasmids were delivered to the intrathecal space of the lumbar spinal region in rats. Lumbosacral CSF was then collected at various time points afterwards for monitoring of cytokines and transgene expression.
Results
This work demonstrates, for the first time, increased tumor necrosis factor‐α and interleukin‐1 in response to intrathecal plasmid vector injection and provides evidence indicating that this response is largely absent in a CpG‐depleted vector. Transgene expression in the CSF is not significantly affected by this immune response. Expression after intrathecal plasmid injection is variable across rats but correlates with the amount of tissue associated plasmid and is increased by disrupting normal CSF flow.
Conclusions
The data obtained in the present study indicate that plasmid immunogenicity may affect intrathecal plasmid gene therapy safety but not transgene expression in the CSF. Furthermore, the development of methods to prevent loss of plasmid via CSF flow out of the central nervous system through the injection hole and/or natural outflow routes may increase intrathecal plasmid gene delivery efficacy. Copyright © 2009 John Wiley & Sons, Ltd. |
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Bibliography: | ark:/67375/WNG-FQFKV712-F ArticleID:JGM1364 NIH - No. GM29090; No. DA024044; No. DA015642; No. NIDA 018156 Supporting Information istex:2A0285B9C0690963497F6FF4B12AC8AEBD26A508 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
ISSN: | 1099-498X 1521-2254 1521-2254 |
DOI: | 10.1002/jgm.1364 |