Engineered Neural Progenitor Transplants in Combination with Exercise to Maximize Neuropathic Pain Reduction Following SCI
Abstract
Spinal cord injury (SCI) produces a multitude of neuropathological issues and consequent clinical challenges in achieving the optimal beneficial outcomes without uncovering or compounding additional complications. While locomotor impairment is a hallmark of SCI, a majority of patients with SCI also report suffering from chronic pain, which further diminishes their quality of life, impacting productivity and participation in normal daily activities, and places tremendous additional burden on families and caregivers. In some ways, the presence of both locomotor impairment and chronic pain lead to a vicious circle, with one exacerbating the other; participation in rehabilitative therapies can provide therapeutic benefits including reduced pain, reduced muscle atrophy, and potential locomotor improvement, while the presence of pain can limit willingness to participate in rehabilitative therapies, resulting in reduced long-term improvement in locomotor function. Even though research has demonstrated that complementary therapies that target multiple aspects of an injury enhance recovery, most studies have given little attention to the potential for synergistically improved locomotor and neuropathic pain recovery. The proposed work will explore a more complete approach towards restoring quality of life in SCI patients by designing a therapy that addresses three main issues associated with SCI in order to maximize pain reduction and locomotor recovery. One issue underlying SCI pain is that the injury results in dysfunctional inhibitory (GABA) and excitatory (NMDA) signaling, partially due to lost or damaged cells. Unfortunately, pharmacologic targeting of these systems presents significant challenges in current clinical practice owing in part to undesirable systemic side effects. Direct targeted therapies such as cellular transplantation can replace lost and damaged cells, thus avoiding systemic issues associated with pharmacotherapy. Further, cellular transplants can be engineered to provide a long-term, continually renewable source of therapeutic peptides. Towards this end, our lab has been exploring spinally directed cellular transplantation of neural progenitor cells (NPCs) to replace lost GABA cells for alleviation of chronic pain. These cellular transplants have also been engineered to produce additional analgesic peptides such as NMDA antagonists to further provide analgesics and address the dysfunctional spinal signaling. Clinically, locomotor training (LT) such as treadmill training has become one of the most promising adjunct therapies for SCI. LT, which relies on intrinsic and automatic control of locomotion by lower neural circuits, is currently utilized to improve functional recovery in SCI patients and to treat some types of peripheral neuropathic pain. Aside from the these benefits, recent discoveries on SCI-associated pain have shown that LT with moderate exertion reduced some symptoms, and increased exertion under an intensive locomotor training (ILT) protocol designed by our laboratory provided improved analgesic effects. Neurochemical mechanisms associated with the functional and analgesic benefits of LT include changes in expression of neurotrophic factors, endogenous opioids, serotonin, and markers of inflammation. These changes help support spinal plasticity, reorganization, and learning, leading to improved functional and neuropathic recovery. Taken together, these data suggest that ILT is a promising addition to current and novel therapeutic options such as our cellular transplantation. This proposed translational work will examine a combination therapy of GABAergic cellular transplantation (with or without production of an NMDA antagonist) combined with ILT to maximize pain reduction and enhance functional recovery following incomplete SCI. We hypothesize that the proposed combination therapy will promote improved recovery based on its design to target spinal cord dorsal horn dysfunctio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610683
Entities
People
- Jacqueline Sagen
Organizations
- United States Army
- University of Miami