The present proposal is a competing renewal of a Stage II NIDA Cutting Edge Basic Research Award (CEBRA).
Its aims are focused on developing a new therapy for persistent pain relief. Persistent pain (3+ months) is a common, unresolved health problem in Americans. A recent consideration in our understanding of neuropathic pain (pathological neuronal signaling in the pain pathway) includes the contribution of immune cells &glia (astrocytes, microglia, Satellite &Schwann) in pain relevant compartments such as the spinal cord dorsal horn, spinal meninges associated subarachnoid matrix, &dorsal root ganglia. Spinal cord glia mediate pathological pain via the release of well-characterized proinflammatory cytokines. The anti-inflammatory cytokine, interleukin-10 (IL-10), potently inhibits proinflammatory cytokine actions. During the current grant period, data strongly support spinal subarachnoid (intrathecal;IT) gene delivery of IL-10 prevents &reverses pathological pain in animal models. Long-duration (3+ months) pain relief is achieved upon 2 sequential IT injections of non-viral vectors, where the 2nd injection must encode IL-10 (plasmid DNA encoding IL-10;pDNA- IL-10). The first injection serves to sensitize the spinal subarachnoid compartment to the 2nd injection that creates IL-10-dependent long-duration pain relief. A robust accumulation of glia, macrophage &/or dendritic cells are components of sensitization. IL-10 protein signaling during the sensitization interval is necessary for long-duration IL-10 gene therapy. We postulate that several immune interrelated etiologies, including chemotaxis, mitosis, &phagocytosis play critical roles for sensitization &IL-10 transgene uptake. Thus, activated (chemotactic &/or mitotic) immune cells &glia could be responsible, in part, for the sensitized response to pDNA-IL-10 uptake. An FDA-approved synthetic polymer improves pDNA-IL-10 drug delivery after a single injection at reduced dosage formulations. However, further improvement is needed for clinical trials. Identifying the anatomical region, cell type and cellular activity underlying sensitization can be exploited to further improve polymer spinal IL-10 targeted gene delivery.
The aims of the present proposal are straightforward: (1) To identify the cellular/biochemical responses in pain-relevant regions during sensitization;(2) To examine whether the cellular/biochemical profiles important during sensitization are also necessary during long duration gene expression and pain relief;and (3) To further improve IT gene delivery using PLGA- pDNA-IL-10 formulations that include co-release of factors important during sensitization &long-duration gene expression such that enduring pain relief can be achieved from a single injection.

Public Health Relevance

Spinal subarachnoid gene delivery of the anti-inflammatory cytokine, interleukin-10 (IL-10), potently inhibits proinflammatory cytokine actions and produces long-duration (3+ months) pain relief of 2 sequential IT injections of non-viral vectors, where the 2nd injection must encode IL-10 (plasmid DNA encoding IL-10;pDNA- IL-10). The inter-injection interval is characterized as a sensitization period of the spinal subarachnoid compartment to the 2nd injection that creates IL-10-dependent long-duration pain relief &may involve immune interrelated etiologies, including chemotaxis, mitosis, &phagocytosis. Although, further improvement is needed for clinical trials, preliminary studies show an FDA-approved synthetic polymer improves pDNA-IL-10 drug delivery after a single injection at reduced dosage formulations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018156-09
Application #
8299615
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Thomas, David A
Project Start
2004-09-20
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$322,029
Indirect Cost
$90,324
Name
University of New Mexico Health Sciences Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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Sloane, Evan; Ledeboer, A; Seibert, W et al. (2009) Anti-inflammatory cytokine gene therapy decreases sensory and motor dysfunction in experimental Multiple Sclerosis: MOG-EAE behavioral and anatomical symptom treatment with cytokine gene therapy. Brain Behav Immun 23:92-100
Hughes, Travis S; Langer, Stephen J; Virtanen, Salla I et al. (2009) Immunogenicity of intrathecal plasmid gene delivery: cytokine release and effects on transgene expression. J Gene Med 11:782-90
Sloane, E; Langer, S; Jekich, B et al. (2009) Immunological priming potentiates non-viral anti-inflammatory gene therapy treatment of neuropathic pain. Gene Ther 16:1210-22

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