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Exploring the use of synthetic delivery platforms and small molecule adjuvants to improve the efficacy of spinal interleukin-10 gene therapy for chronic neuropathic pain


Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/21024

Exploring the use of synthetic delivery platforms and small molecule adjuvants to improve the efficacy of spinal interleukin-10 gene therapy for chronic neuropathic pain

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dc.contributor.author Dengler, Ellen
dc.date.accessioned 2012-08-27T22:38:03Z
dc.date.issued 2012-08-27
dc.date.submitted July 2012
dc.identifier.uri http://hdl.handle.net/1928/21024
dc.description.abstract The focus of the work in this dissertation is to improve the efficiency of a gene therapy for the treatment of chronic pain. The introduction, Chapter 1, is intended to orient the reader to the underlying physiological principles and anatomical structures involved in general sensory and pain transmission in the peripheral and central nervous systems. Pain modulatory systems are described in detail. Also included is a discussion of how peripheral nerve injury can provoke immune changes at the spinal level, including the activation of spinal macrophages and glial cells (microglia, astrocytes and oligodendrocytes) with the release of immune modulators, such as pro- and antiinflammatory cytokines, that can lead to the development of chronic pain. One of the most important of these is the anti-inflammatory cytokine, Interleukin-10 (IL-10). As a framework for the experiments described in the dissertation, earlier studies using spinal injections of IL-10 protein and DNA containing the gene for IL-10 for the treatment of neuropathic pain in a chronic constriction injury (CCI) rodent model are introduced. Also presented in this dissertation, are some of the key problems of delivering DNA to cells (tranfection). The studies in Chapter 2 explore the use of one novel non-viral synthetic platform, a silica/lipid nanoparticle or “protocell,” as a potential platform for IL-10 transgene delivery to the central nervous system (CNS). These particles had never before been examined in vivo in the CNS. The first objective was to determine if they simply would be tolerated by animals following peri-spinal injection. The second objective was to determine their biodistribution in the whole body following these injections and the cell type interacting with them near the spinal injection site. The final objective was to determine if the IL-10 transgene produced functional IL-10 protein following loading on protocells and if the gene loaded on protocells would produce a therapeutic pain reversal in neuropathic animals. The studies in Chapter 3 are based on previously published results of a critical interval following spinal injection of a transgene, the “sensitization period”, during which there is immune cell enrichment in the cerebral spinal fluid (CSF) in the subarachnoid matrix. This local enrichment of immune cells in the spinal CSF, is key to the development of the experimental approach used in Chapter 3, which is to prime improved cellular uptake of the IL-10 gene with small molecules as immune adjuvants. In Chapter 2 and Chapter 3, each experimental data set is presented in the form of the original manuscripts, submitted for external peer-review and publication. Chapter 4 includes a discussion of the gene therapy approaches used in this work and by other investigators. Also considered are some future directions, including the use of a different synthetic polymer, polylactic co-glycolic acid, PLGA, that is FDA approved and highly biodegradable in the body. A concluding statement completes the work of this dissertation. en_US
dc.description.sponsorship National Institue of Health; National Science Foundation Fellowship: Integrative Graduate Educational and Research Traineeship en_US
dc.subject neuropathic pain en_US
dc.subject gene therapy en_US
dc.subject chronic constriction injury en_US
dc.subject nanoparticles en_US
dc.subject adjuvants en_US
dc.subject protocells en_US
dc.subject mesoporous silica en_US
dc.subject interleukin-10 en_US
dc.subject.lcsh Chronic pain--Gene therapy.
dc.subject.lcsh Interleukin-10.
dc.subject.lcsh Transfection.
dc.subject.lcsh Immunological adjuvants.
dc.title Exploring the use of synthetic delivery platforms and small molecule adjuvants to improve the efficacy of spinal interleukin-10 gene therapy for chronic neuropathic pain en_US
dc.type Dissertation en_US
dc.description.degree Biomedical Sciences en_US
dc.description.level Doctoral en_US
dc.description.department University of New Mexico. Biomedical Sciences Graduate Program en_US
dc.description.advisor Milligan, Erin
dc.description.committee-member Wallace, James
dc.description.committee-member Cunningham, Lee Anna
dc.description.committee-member Brinker, C.Jeffrey
emb.embargo.terms 2014-07-30
emb.embargo.lift 2014-07-30

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