A Novel Combinatorial Therapy Targeting Neuroplasticity to Promote FunctionalRecovery in Chronic Spinal Cord Injury

About This Grant

Project Summary/Abstract The frequency of US soldiers suffering a contusive thoracic spinal cord injury (SCI) is increasing. A contusion to the spinal cord damages nervous tissue causing motor function impairments. There is little natural repair; functional deficits are mostly permanent. Current treatments for acute SCI are limited in restoring function. As a result, there are over 42,000 Veterans in the VA Health System living with the consequences of long-term chronic contusion SCI. There is a clear and urgent need for treatments that recover function in long-term chronic SCI. The motor deficits in chronic contusion SCI are due in large part to damaged motor axons that in the early phases after injury were unable to grow and integrate into the axonal circuits that generate muscle movements. Axon growth is an important predictor of neurological outcome after SCI. Promoting axon growth may support functional recovery in long-term chronic contusion SCI. However, axon growth in a long-term chronically contused spinal cord is impeded by a collapsed injury site with cystic cavities and a fully matured glial scar with abundant growth-inhibitory chondroitin sulfate proteoglycans (CSPGs). Also, chronically-injured upper motor neurons (UMN), which give rise to motor axons in the spinal cord, may exhibit low growth competence due to long-term down regulation of their intrinsic growth programs. These concurrent extrinsic neural and intrinsic neuronal aspects of chronic spinal cord contusion injury each need to be addressed to maximize axon growth and so the prospect of functional recovery for our chronically injured Veterans. We present a potential solution in the form of a ‘gel-cell’ therapy to address the non-conducive, hostile axon growth conditions in long-term chronic contusion SCI. We injected a combination of nanofiber hydrogel composite (NHC, ‘gel’) with Schwann cells (SCs, ‘cell’) into a chronic thoracic contusion in adult rats and showed that the gel-cell facilitated tissue formation in the contusion site, provided spinal cord integrity, promoted axon growth, and improved hindlimb function recovery. The use of NHC and SCs as a gel-cell therapy for long-term chronic SCI has not been studied before. Here, we will use an adult rat model of long-term chronic (6 months) contusion SCI to: 1) enhance our understanding how NHC affects transplanted SCs; 2) strategize the gel-cell therapy effectively to maximize the axon growth response and motor recovery. In Specific Aim 1, we will study if NHC maintains the ability of SCs in a long-term chronic contusion site to produce the axon growth-stimulating neurotrophic factors, BDNF and NGF. We will also explore the possible role of CSPGs in down regulating neurotrophin production in transplanted SCs. In Specific Aim 2, we will study how treatment with intracellular sigma peptide, to block CSPG-mediated axon growth inhibition, and possibly down regulation of SCs’ neurotrophic factor production, affects axon growth and hindlimb motor function in rats with NHC/SC-treated chronically contused SCI. The effects of rehabilitative treadmill training on translation of axon growth response into hindlimb motor function will be studied. The Specific Aims will test the central hypothesis that in long-term chronic spinal cord contusion injury, SCs in NHC/SC therapy maintain their ability to produce neurotrophic factors, in part by limiting CSPG-mediated neurotrophic factor down regulation, thereby stimulating motor axon growth, which can be further enhanced by interfering in glial scar-associated growth inhibition and rehabilitative exercise. Our mechanistic and functional studies will provide insight in the repair potential of SC and especially the NHC/SC therapy for long-term chronic contusion SCI, and develop strategies to maximize motor recovery. The data from our studies may form the foundation of future clinical therapies for improving motor function, which will have great impact on the quality of life of our Veterans with long-term chronic contusion SCI.