Neurogenic pain resulting from injury to the nervous system is often persistent and debilitating, and presents a significant clinical challenge as it does not respond well to traditional therapies. Novel interventive strategies using cellular transplantation into the spinal cord have been explored to provide a local and continually renewable source of analgesic agents and neurotrophic factors or to replace lost cellular populations. However, the selection of appropriate cells for transplantation is challenging, due to limitations in human organ donor availability, immunogenicity, and potential disease transmission. The goal of this R21 Exploratory grant proposal is to evaluate the feasibility of using autologous stem cell-like bone marrow cells as vehicles for delivering analgesic agents to local spinal sites for alleviation of neurogenic pain. The use of autologous cells that can be expanded ex vivo would overcome the limitations associated with other donor sources, as well as the potential ethical objections surrounding the use of embryonic stem cells. In addition, bone marrow stromal cells have been shown to migrate selectively and """"""""home"""""""" to damaged regions of the CMS when injected intravenously, and thus may offer a minimally invasive grafting approach. In order to evaluate this approach for pain due to peripheral or central injury, a unique subpopulation of human bone marrow stromal cells which have been shown to exhibit embryonic stem cell self-renewal and differentiation properties (named the Marrow-Isolated Adult Multilineage Inducible or MIAMI cells), will be used. Cells will be administered intravenously or intrathecally and assessed for their ability to target the spinal cord and to deliver analgesic agents using two distinct models of neurogenic pain: the quisqualic acid (QUIS) model for excitotoxic spinal cord injury pain and the chronic constriction injury (CCI) model for peripheral neuropathic pain. The first produces a fairly large lesion site associated with overt neuronal loss in the dorsal horn, while the second produces a more subtle pathology and reorganization in the dorsal horn, both resulting in abnormal pain processing including allodynia, hyperalgesia, and dysesthesias.
Two specific aims are proposed; the first to evaluate the ability of the MIAMI cells to home to sites of pathology in the dorsal horn following QUIS or CCI, and the second to evaluate potential cell-mediated delivery of analgesic agents to these sites using cells engineered to produce proenkephalin as a proof of concept. Evaluations will include alterations in pain behaviors, host-graft integration, spinal neurochemistry, and potential pathology. If successful, findings from these studies should lead to development of novel and potent strategies in the management of chronic neurogenic pain.
|Gajavelli, Shyam; Castellanos, Daniel A; Furmanski, Orion et al. (2008) Sustained analgesic peptide secretion and cell labeling using a novel genetic modification. Cell Transplant 17:445-55|