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2013
Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI
Posted April 4, 2013
Gordon Mitchell, Ph.D., University of Wisconsin, Madison;
Gillian Muir, D.V.M., Ph.D., University of Saskatchewan;
Randy Trumbower, Ph.D., Emory University
Spinal cord injury (SCI) disrupts the connections between the brain and spinal cord, leading to lifelong paralysis in soldiers. However, many spinal cord injuries are incomplete, leaving at least some spared neural pathways to the motor neurons that initiate and coordinate movement. Consequently, spinal plasticity can contribute to spontaneous recovery of limb and respiratory function following SCI. Unfortunately, spontaneous recovery is slow, variable, and of limited extent. Dr. Gordon Mitchell, Dr. Gillian Muir, and Dr. Randy Trumbower received a Translational Research Partnership Award from the Fiscal Year 2010 Spinal Cord Injury Research Program to study the potential value of repeated acute intermittent hypoxia (AIH), alone or in combination with locomotor training, for improving limb function in animals with chronic SCI. They are applying AIH to elicit cellular and synaptic mechanisms of spinal plasticity in non-respiratory motor neurons, and hope to determine whether it can improve leg function in patients with chronic, incomplete SCI. Preliminary animal experiments have shown that AIH combined with daily training elicits sustained improvement in limb motor function of treated animals with chronic cervical SCI. In addition, preliminary clinical studies reveal a sustained increase in walking speed and distance following a 10-meter walk test and a 6-minute walk test, respectively. If successful, AIH could represent a novel method for stimulating spinal plasticity in individuals with SCI, providing an avenue for controlled restoration of motor neuron excitability, and eventual restoration of volitional movement after incomplete SCI.
Links:
Public and Technical Abstracts: Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI
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Matrix Metalloproteinases as a Therapeutic Target to Improve Neurologic and Urologic Recovery after Spinal Cord Injury
Posted January 3, 2013
Linda Noble, Ph.D. University of California, San Francisco
Jonathan Levine, DVM, Texas A & M
Despite decades of effort being dedicated to developing therapeutics for spinal cord injury (SCI), a robust clinical treatment remains elusive. Following acute SCI, matrix metalloproteinases (MMPs) are upregulated and promote early inflammation and disrupt the extracellular matrix (ECM) and the blood-spinal cord barrier. Dr. Linda Noble has received a Fiscal Year 2010 Investigator-Initiated Research Award to study the efficacy of an MMP inhibitor in a mouse model of SCI as well as a larger animal model with naturally occurring SCIs as the result of spontaneous rupture of an intervertebral disk. Newly completed studies in mice subjected to a relatively severe SCI show that the MMP inhibitor therapy, when given 8 hours post injury, results in improved neurological outcome by 6 weeks. Moreover, bladder function, assayed by awake cystometry, is also improved as evidenced in part by a reduction in uninhibited bladder contractions and residual urine. Dr. Noble has entered into collaboration with Dr. Jon Levine at Texas A&M University to determine the efficacy of the MMP inhibitor in a second animal model of SCI. The safety and appropriate drug dosing parameters of the MMP inhibitor have been established in uninjured animals. Baseline urodynamic data have been collected in both uninjured animals and animals with acute SCI. The unique two species design of this study will enable the rapid preclinical optimization of a promising MMP inhibitor for the treatment of SCI. If these preclinical studies in animal models are successful, this compound could be quickly transitioned into human clinical trials.
Links:
Public and Technical Abstracts: Matrix Metalloproteinases as a Therapeutic Target to Improve Neurologic Recovery after Spinal Cord Injury
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2012
Improving the Care of Individuals with SCI/TBI Dual Injury
Posted October 5, 2012
Drs. Michael Beattie and Geoffrey Manley, University of California, San Francisco
Dr. Graham Creasey, VA Health Care System, Palo Alto
Spinal cord injury (SCI) is often accompanied by traumatic brain injury (TBI), which complicates treatment in both the critical care and rehabilitation settings. Validated treatment approaches for this dual diagnosis, however, are lacking. Drs. Beattie, Manley, and Creasey received a FY09 Translational Research Partnership Award to initiate a bedside to bench to bedside strategy for improving the clinical care of individuals with SCI/TBI dual injury. They queried the clinical community, including participants at the Santa Clara Valley Brain Injury Conference, to gather information on the current treatment strategies for SCI/TBI dual injury, and to determine what they feel are the greatest needs for this population. Survey responses revealed that a majority of clinicians feel that there is a strong need for more research to improve the care of individuals with SCI/TBI dual injury, and that animal models of hand function may motivate changes in clinical practice. Additional clinical information is being gathered from several national and local databases of SCI and TBI clinical care and patient outcomes to identify factors that may affect recovery, including type and extent of injury, medical complications, Functional Independence Measure, and other factors that affect recovery. All of this information will help to inform the development and characterization of SCI/TBI animal models. To establish a baseline for future models, the investigators utilized currently available protocols to create rat models of incomplete SCI plus mild-complicated and moderate TBI. The development of additional models will be based on the needs of the clinical community, and will be used to evaluate clinic-driven hypotheses for new critical care and rehabilitation strategies for SCI/TBI dual injury. To bring the project full circle, data derived from the animal studies will be used to propose improved guidelines clinical treatment. This partnership has developed a community of researchers and clinicians working together to improve the care and treatment of individuals with SCI and TBI.
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Advanced Development of a Therapeutic, Humanized, Anti-Inflammatory Antibody: A Novel Neuroprotective Treatment that Improves Outcomes after Spinal Cord Injury
Posted August 21, 2012
Gregory Dekaban, Ph.D., and Arthur Brown, Ph.D., University of Western Ontario
Trauma to the central nervous system (CNS) initiates tissue responses that include swelling and inflammation. Inflammation, in turn, causes damage to surrounding tissues, resulting in secondary injury and increased loss of neurological function. It is critical, therefore, to treat for inflammation as soon as possible following SCI in order to protect undamaged neurological tissues and improve recovery and long-term functionality. Previous studies in animal models have shown that treatment with a monoclonal antibody against the immune cell protein CD11d reduces systemic inflammatory response after CNS trauma, and improves recovery. Drs. Dekaban and Brown received an FY09 Advanced Technology/Therapeutic Development Award to advance a humanized anti-CD11d antibody into clinical trials. In the first year of this award, the team has developed assays to measure the serum concentration of anti-CD11d after treatment, to characterize the antibody's activity, and to determine the subject's biological response to this treatment. The team also compared the effectiveness of several anti-CD11d antibodies of increasing affinity in a rat model and identified the most effective antibody for reducing inflammation and improving neurological recovery. Experiments are in progress to optimize the dosing schedule for this antibody treatment in the rat SCI model. To aid in further analysis of this antibody, Drs. Dekaban and Brown are developing additional animal models for testing in different types and degrees of SCI and are developing new functional measurements, including behavioral scales for locomotion and treadmill training in a larger animal model of SCI. These preclinical studies of anti-CD11d antibodies in animal models of SCI will pave the way to translating this promising therapeutic for human use.
Links:
Public and Technical Abstracts: Advanced Development of a Therapeutic, Humanized, Anti-Inflammatory Antibody: A Novel Neuroprotective Treatment that Improves Outcomes after Spinal Cord Injury
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Schwann Cell Implantation for SCI Repair: Optimization of Dosing, Long-Term Cell Persistence, and the Evaluation of Toxicity and Tumorigenicity
Posted August 7, 2012
Damien D. Pearse, Ph.D., Mary Bartlett Bunge, Ph.D., and James Guest, M.D., Ph.D., University of Miami School of Medicine
Individuals with spinal cord injury (SCI) endure lifelong complications from their injury. New strategies to repair the injured spinal cord and effectively restore function following SCI are greatly needed. Schwann cells, a key component of the peripheral nervous system, have been shown to be effective in promoting axon growth, remyelination, and functional recovery in many SCI models, and may serve as effective cell therapy in humans. To avoid the need for immune suppression, Schwann cells can be derived in large numbers from an individual with SCI, expanded and purified in culture, and then implanted in the same individual. Drs. Pearse, Bunge, and Guest received an FY09 Advanced Technology/Therapeutic Development Award to perform dosage, safety, and toxicity studies of Schwann cell implantation in animal models of SCI in preparation for human clinical trials. Optimal dose was obtained in a thoracic contusion (T8) rat model based on functional recovery over a course of 12 weeks after implantation. The investigators demonstrated that transplanted human Schwann cells survived for up to 6 months, the longest time examined, and were not associated with tumor formation, additional tissue damage, scarring, or adverse immune responses. The extent of axon growth into the spinal cord lesion correlated with the number of persisting human Schwann cells present in the animals. Importantly, locomotor function was significantly improved in injured rats treated with Schwann cells compared to injured controls. These promising results allowed the team to submit an application to the Food and Drug Administration to begin a clinical safety trial in humans.
Links:
Public and Technical Abstracts: Schwann Cell (SC) Implantation for SCI Repair: Optimization of Dosing, Long-Term Cell Persistence, and the Evaluation of Toxicity and Tumorigenicity
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Brain-Controlled Intrafascicular Nerve Stimulation with High-Count Electrode Arrays for Producing Coordinated Hand Movements
Posted July 18, 2012
Gregory A. Clark, Ph.D., University of Utah, Salt Lake City, Utah
Lee E. Miller, Ph.D., Northwestern University, Chicago, Illinois
The single most difficult injury to surmount for many individuals with spinal cord injury is the loss of hand function. Although some restoration of hand use has been obtained through functional electrical stimulation techniques, the resulting movements are limited, difficult to control, and fatigue muscles easily. In Fiscal Year 2009, Dr. Gregory Clark received an Investigator-Initiated Research Award through the Spinal Cord Injury Research Program to develop an improved approach to restoring coordinated hand function following paralysis. In collaboration with Dr. Lee Miller at Northwestern University School of Medicine, Dr. Clark will implant high-channel-count Utah Slanted Electrode Arrays (USEAs) into the peripheral forearm nerves of an animal model to activate paralyzed muscles. The intrafasicular implantation of USEAs will facilitate the activation of motor units of multiple forearm, wrist, and hand muscles selectively and independently, leading to more coordinated and graded movements with a reduced risk of fatigue. Drs. Clark and Miller have performed the first-ever chronic implantation of USEAs in the median nerve of two animal preparations, with little initial adverse reaction. Three months following USEA implantation, compound action potentials were evoked in arm muscles following nerve stimulation by USEA electrodes. In future planned experiments, signals recorded directly from motor cortex with Utah Electrode Arrays will be used to drive the stimulation of the USEA to produce movement despite a temporary, nerve-block-induced paralysis of the forearm and hand. The performance on trained motor behaviors, such as individual digit flexions and grasp-and-placement tasks, will be used to evaluate performance of cortical control of the implanted USEA, and will provide feedback for the researchers to fine-tune the system. If successful, this novel brain-machine interface will provide a means of restoring voluntary control of paralyzed muscles following spinal cord injury.
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2011
Obesity/Overweight in Persons with Early and Chronic SCI: A Randomized Multi-Center Controlled Lifestyle Intervention
Posted December 1, 2011
Mark S. Nash, Ph.D., FACSM, Miller School of Medicine, University of Miami, Miami, Florida
Obesity is a serious, and worsening, health concern for both military personnel and civilians with spinal cord injuries (SCI). A series of reports from 1994-1995 estimate that the rate of obesity is up to 66% higher in persons with disabilities than in non-disabled individuals. In addition to increasing risk for cardiovascular and metabolic diseases, obesity in SCI patients can lead to diminished work capacity, musculoskeletal strain, increased pain, worsening of neurological status, and life dissatisfaction. Dr. Mark Nash, at the University of Miami Miller School of Medicine, has received a Fiscal Year 2009 Spinal Cord Injury Research Program Clinical Trial Award - Rehabilitation to perform a multi-center randomized clinical trial evaluating a lifestyle intervention aimed at decreasing obesity in persons with SCI. This study will be conducted at two SCI rehabilitation centers and two VA Medical Centers and is expected to enroll a total of 64 individuals with SCI who are overweight or obese and have fasting glucose and lipid levels that are outside the accepted healthy ranges. Participants will be monitored for 6 months by lifestyle coaches who will personalize either a structured lifestyle intervention (circuit resistance training, calorie-matched Mediterranean-style diet, and behavioral support) or an exercise plan with non-diet behavioral support. At the end of the 6-month lifestyle intervention or exercise program, participants will be followed for a year while treatments are performed at home or in community-based centers. The primary goal of this study is to demonstrate a sustained weight loss of 7% body weight, an amount that has been previously shown to decrease risk of diabetes. Additional outcomes that will be measured for all participants include body fat percentage, overall fitness, glucose and lipid profiles, and perceived quality of life. This study will provide the necessary evidence to initiate health reform and improve weight management strategies for persons with SCI in both military and civilian settings.
Links:
Public and Technical Abstracts: Obesity/Overweight in Persons With Early and Chronic SCI: A Randomized, Multicenter, Controlled Lifestyle Intervention
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SCI Survey to Determine Pressure Ulcer Vulnerability in the Outpatient Population
Posted January 6, 2011
Lisa Gould, M.D., Ph.D., James A. Haley Veterans' Hospital, Tampa, Florida
Pressure ulcers, one of the most common long-term complications of spinal cord injury (SCI), are areas of tissue damage that occur as a result of interrupted blood circulation. Healthy individuals are able to make unconscious accommodations when decreases in tissue blood flow due to pressure are detected, but this feedback does not work as well in persons with SCI, who often have reduced or absent sensation and limited mobility. Pressure ulcers (PrUs) can result in weeks or months of bed confinement, rehabilitation setbacks, loss of employment and income, loss of social interaction, and decreased quality of life. While the risk remains high, not all SCI patients have the same propensity for developing PrUs. Dr. Lisa Gould, of the James A. Haley Veterans' Hospital (JAHVH), received an Exploration - Hypothesis Development Award from the Department of Defense Fiscal Year 2009 Spinal Cord Injury Research Program to identify the demographic, biophysical, and psychosocial factors that increase risk of PrUs in persons with SCI. This study will begin with a retrospective medical chart review of 60 patients from the JAHVH Spinal Cord Injury System of Care to refine the list of potential risk and protective factors. Next, anthropometric measurements will be taken using musculoskeletal ultrasound in individuals without PrUs, those that have had recurring PrUs, and those that have had one or two PrUs but have healed and remain healthy. Finally, a prospective survey of 800 SCI patients coming to JAHVH for their annual exams will be conducted. Together these data will lead to the identification of factors that are protective against the development of PrUs, allowing for improved risk assessment and customized interventions for individuals with SCI.
Links:
Public and Technical Abstracts: SCI Survey to Determine Pressure Ulcer Vulnerability in the Outpatient Population
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