Posted August 8, 2013
In 2009 Congress first appropriated $35M for the Spinal Cord Injury Research Program (SCIRP) to support research projects that have the potential to make a significant impact on improving the health and well-being of military Service members, Veterans, and other individuals living with SCI. A total of $97.85 million (M) has been appropriated through fiscal year 2013. These funds have supported projects directed toward the continuum of acute care, through rehabilitation, adjustment to disability, and chronic complications of SCI. While most of the studies funded are still ongoing, several projects have shown great promise for improved functional recovery and quality of life after SCI. This summary highlights the broad scope of the SCIRP portfolio, and some of the recent research progress of SCIRP-funded investigators.
Effective early intervention strategies that can be implemented within hours after SCI are essential to minimize damage and mitigate secondary injury that results through inflammation, infection, and other environmental and micro-environmental factors. Several SCIRP investigators are developing therapies that can be administered during this critical time period. For example, Dr. Adina Michael-Titus, a Fiscal Year 2009 (FY09) Investigator-Initiated Research Award (IIRA) recipient, demonstrated that treatment with docosahexaenoic acid (DHA, an omega-3 polyunsaturated fatty acid) within 30 minutes after contusion injury resulted in significant locomotor improvement in mice as early as 11 days post-injury. In another study, Dr. Linda Noble, a FY10 IIRA recipient, found that administration of a matrix metalloproteinase (MMP) inhibitor administered in an animal model 8 hours post SCI resulted in improved neurological outcome by 6 weeks.
Altering the lesion microenvironment to improve regenerative capability is a common theme across a number of SCIRP awards. Chondroitin sulfate proteoglycans (CSPGs) are a target of two FY09 IIRA recipients, as their long sugar chains have been shown to inhibit neural regeneration. Dr. Victor Arvanian is studying the mechanism(s) underlying these inhibitory actions in the lesion site, and is evaluating antibody treatment against specific CSPG chains to repair transmission along spared fibers. He has demonstrated that a single acute administration of an antibody to the NG2 chain restores the neural deficits induced by NG2. Dr. Diane Snow has prepared purified enzymes to naturally degrade the CSPGs and promote neural regeneration. Other damaging environmental conditions within the lesion site that are being addressed by SCIRP investigators include inflammation, high acidity, damaged cell membranes and fatty acid imbalances, disrupted vascular networks, and excess blood, which can lead to hemorrhagic necrosis.
Medical management of SCI in the acute setting is also an area of interest for the SCIRP, as evidenced by two FY12 studies just getting underway. Dr. Jean-Marc Mac-Thiong is evaluating the optimal temporal setting for surgical intervention after SCI, hypothesizing that early intervention will have a positive impact on functional status and neurological recovery, as well as length of hospital stay and overall costs. In a separate study, Dr. Michael Beattie will retrospectively evaluate early management of blood pressure for correlation with outcomes, followed by prospective monitoring of SCI patients under intensive care.
Rehabilitation and Adjustment to Disability
As individuals with SCI transition from acute care to the rehabilitation phase, they face many new challenges. Not only are they adjusting to their sudden limitations in mobility, but many are also experiencing secondary physical and neurological complications, including loss of bone mass and quality, muscle spasticity, autonomic dysreflexia, bladder and bowel dysfunction, sexual dysfunction, pain and sensory dysfunction, respiratory dysfunction, and increased susceptibility to pressure ulcers. This adjustment is often a difficult one, and to gain a better understanding of these experiences, the SCIRP has invested in several qualitative research studies to examine the thoughts, decisions, behaviors, goals, and biggest challenges for individuals with SCI, as well as their caregivers. These efforts will hopefully help researchers and clinicians identify the most effective paths for adjusting to and/or improving life with disability
The SCIRP has focused much of its support toward rehabilitation efforts and developing therapies and tools to mitigate dysfunction and improve functional recovery. Among these efforts are a couple of projects under the Clinical Trial Award - Rehabilitation (CTA-R) mechanism focused on mitigating bone loss, and increasing bone mass, quality, and architecture. Dr. Thomas Schnitzer is evaluating the combined effect of vibration therapy with administration of parathyroid hormone, and measuring the effects on bone using magnetic resonance imaging (MRI) and serum bone biomarkers. Dr. Leslie Morse is conducting a study to test the combined effect of functional electrical stimulation rowing with zoledronic acid (a bisphosphonate), and early results suggest an increase in bone volume and stiffness due to row training.
Cell based therapies are an area showing great promise. Drs. Damien Pearse, Mary Bunge, and James Guest received an FY09 Advanced Technology/Therapeutic Development Award (AT/TDA) 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, and locomotor function was observed to improve significantly. A Phase I clinical trial is now in progress to evaluate safety in individuals with sub-acute SCI.
Chronic Secondary Complications
Over a dozen SCIRP funded projects are focused on autonomic dysreflexia and/or bladder and bowel dysfunction, as this is a critical complication that affects qualify of life. Dr. Naoki Yoshimura received an FY10 IIRA to study intrathecal application of nerve growth factor (NGF) antibodies to reduce bladder overactivity and autonomic dysreflexia in rats. He has found that SCI induces autonomic dysreflexia during bladder distention, and that treatment with NGF antisense successfully suppresses bladder overactivity.
Sexual dysfunction is a common neurological complication that is particularly difficult for young men and women. Dr. Raymond Grill received an FY11 IIRA to explore the molecular, biochemical, and structural changes in blood-testis-barrier (BTB) with time after SCI. He will also test Licofelone, and anti-inflammatory drug, for protection of BTB integrity.
Pain is another area that greatly affects quality of life, and is of great interest to the SCIRP. Funded projects in this area include the development and testing of several novel non-opioid drugs, drugs that improve the efficacy of and mitigate the side effects of opioid drugs, deep brain stimulation, barriers and facilitators of coping with pain, and mechanistic studies to better understand how various therapies work against pain.
While immobility increases risk of developing pressure ulcers, some individuals seem more prone (or more resistant) to them than others. Dr. Lisa Gould, an FY09 Exploration-Hypothesis Development Award (EHDA) recipient, has identified and stratified risk factors for pressure ulcer development, and is developing a clinical assessment tool to assist healthcare providers identify individuals at greatest risk. Dr. Stephen Sprigle has received an FY12 award to determine whether weight-shift activities have a protective influence on the skin, and assess the relationship between wheelchair movement and the amount of these weight-shift activities.
Many individuals with SCI experience some form of respiratory dysfunction, with some requiring ventilation management. The studies funded by the SCIRP primarily focus on sleep disordered breathing, including a mechanistic study to determine neural mechanisms for reduced sleep efficiency (Dr. Stefany Primeaux, FY09 EHDA), a clinical study to determine the prevalence of obstructive sleep apnea and to determine reliable clinical predictors (Dr. Robert Sitrin, FY10 CTA-R), and a clinical trial to determine the associations between sleep disordered breathing and cognitive impairments, and the effect of positive airway pressure therapy on cognitive performance, mood, pain, and cardiovascular measures (Dr. Shirin Shafazand, FY12 Clinical Trial Award).
As these SCIRP funded projects continue to mature, we will learn more about the nature and mechanisms of the injuries and secondary complications, and will hopefully see several new successful therapies move forward through the clinical trial process and on to approval by the Federal Drug Administration. True success of our program, however, will be measured by improvement in the lives of American Service members and other individuals impacted by devastating spinal cord injuries.