EXECUTIVE SUMMARY

Spinal cord injuries occur unexpectedly. The normal events of life—driving a car, diving into a lake, or walking down stairs—can suddenly result in a life-changing injury with physical and lifestyle constraints that totally reconfigure the realities of daily life. An estimated 11,000 spinal cord injuries occur each year in the United States, and 247,000 Americans are currently living with a spinal cord injury.

In the past several decades there has been significant progress in improving patient survival and emergency care and in expanding the range of rehabilitative options. During this same time period, the breadth and depth of neuroscience discoveries relevant to spinal cord injury have widely expanded the horizons of potential therapies. What once was dogma—that the central nervous system cannot regenerate—has been dismissed. This newly discovered potential for central nervous system (CNS) regeneration and repair has opened up numerous therapeutic targets and opportunities. Many current avenues of research suggest that a concerted research effort on spinal cord injuries could result in important gains in restoring function and improving quality of life.

Recognizing this wealth of new opportunity, the New York State Spinal Cord Injury Research Board asked the Institute of Medicine (IOM) to examine future research directions in spinal cord injury. The IOM was asked not just to advise New York State on its research program, but to look more broadly at research priorities for funders of spinal cord research—federal and state agencies, academic organizations, pharmaceutical and device companies, and nonprofit organizations. To accomplish this task the IOM appointed a 13-member committee with expertise in basic



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Spinal Cord Injury: Progress, Promise, and Priorities EXECUTIVE SUMMARY Spinal cord injuries occur unexpectedly. The normal events of life—driving a car, diving into a lake, or walking down stairs—can suddenly result in a life-changing injury with physical and lifestyle constraints that totally reconfigure the realities of daily life. An estimated 11,000 spinal cord injuries occur each year in the United States, and 247,000 Americans are currently living with a spinal cord injury. In the past several decades there has been significant progress in improving patient survival and emergency care and in expanding the range of rehabilitative options. During this same time period, the breadth and depth of neuroscience discoveries relevant to spinal cord injury have widely expanded the horizons of potential therapies. What once was dogma—that the central nervous system cannot regenerate—has been dismissed. This newly discovered potential for central nervous system (CNS) regeneration and repair has opened up numerous therapeutic targets and opportunities. Many current avenues of research suggest that a concerted research effort on spinal cord injuries could result in important gains in restoring function and improving quality of life. Recognizing this wealth of new opportunity, the New York State Spinal Cord Injury Research Board asked the Institute of Medicine (IOM) to examine future research directions in spinal cord injury. The IOM was asked not just to advise New York State on its research program, but to look more broadly at research priorities for funders of spinal cord research—federal and state agencies, academic organizations, pharmaceutical and device companies, and nonprofit organizations. To accomplish this task the IOM appointed a 13-member committee with expertise in basic

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Spinal Cord Injury: Progress, Promise, and Priorities and clinical neuroscience research, trauma surgery, health care, biomedical engineering, clinical research methods, and research management. This report by the IOM Committee on Spinal Cord Injury provides a broad overview of the current status of spinal cord injury research, examines the research and infrastructure needs, and provides recommendations for advancing and accelerating progress in the treatment of spinal cord injuries with particular attention to issues regarding translational research. The committee also addresses the contributions that the New York State program can make to complement the scientific efforts of other state, federal, and private supporters of research in this area. DEFINING A CURE Defining what constitutes a “cure” is an integral part of discussions on future directions for spinal cord injury research. In large part, the general public’s perception of a cure for spinal cord injury has been the restoration of motor function, that is, restoration of the ability to walk. However, a spinal cord injury affects many systems and functions of the body that are vital to the health and well-being of the injured person. Neural control of motor, sensory, autonomic, bowel, and bladder functions is compromised, often leading to pain, pressure sores, infection, and diminished physiological well-being. After carefully considering input from the community of individuals with spinal cord injuries, researchers, and clinicians, the committee decided to take a broad approach to “defining a cure” and to frame its definition around alleviating the multiple disabilities that result from spinal cord injury. Spinal cord injury research should focus on preventing the loss of function and on restoring lost functions—including sensory, motor, bowel, bladder, autonomic, and sexual functions—with the elimination of complications, particularly pain, spasticity, pressure sores (decubitus ulcers), and depression, with the ultimate goal of fully restoring to the individual the levels of activity and function that he or she had before injury. By setting forth a set of goals for spinal cord injury research, the committee wishes to emphasize the different stages of the injury during which interventions are needed and the multiple health impairments that affect an individual’s daily quality of life and that require the development of effective therapeutic interventions. IDENTIFYING RESEARCH DIRECTIONS Spinal cord injury results in a cascading biological response ranging from the changes in blood pressure and blood volume and hypoxia (reduc-

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Spinal Cord Injury: Progress, Promise, and Priorities tion of oxygen supply) immediately after the injury is sustained to the subsequent edema, inflammation, and necrotic and apoptotic cell death and, later, to the formation of a glial scar, which can be a barrier to axon regeneration. To regain sensory and motor function, to prevent and eliminate pain, and to retrain and relearn motor tasks will almost certainly demand different treatment strategies and a combination of therapies. A number of therapeutic interventions for spinal cord injuries have been explored over the past several decades. Advances have been made in emergency medical treatment and in rehabilitation efforts, and there is an increased understanding of the specific mechanisms and pathways that are targets for therapeutic interventions. Additionally, recent advances in neuroscience research are opening up new opportunities for the development of therapeutic approaches. Research toward addressing the consequences of spinal cord injuries focuses on a natural progression of strategies: preventing further tissue loss, maintaining the health of living cells, replacing cells that have died through apoptosis or necrosis, growing axons and ensuring functional connections, and strengthening and reestablishing synapses that restore the neural circuits required for functional recovery. These strategies lead to a range of therapeutic targets and priorities for spinal cord injury research (Table ES-1), each of which could theoretically be pursued together with others. For example, cell therapies that replace myelin could be combined with agents such as neurotrophic factors that promote axon regrowth. One of the major challenges in developing combination therapies is determining those specific therapies that are safe for use in combination and that, in concert, will provide the greatest efficacy for the treatment of spinal cord injuries. Although it is possible for different combinations of drugs to be combined by trial and error, greater progress can be made if specific research efforts are devoted to developing and implementing a mechanism to select the most likely components that will be required for combination therapies. This requires a strategic approach to screening and assessing the potentials of the compounds and therapies to be used as components of combination therapies. Much remains to be learned about the basic biology of spinal cord injuries and the numerous potential therapeutic targets involved in the complex processes of maintaining cell and tissue viability and promoting axonal growth and synaptic integrity that will result in improved and appropriate function in individuals with spinal cord injuries. Adding to the body of knowledge on neurological circuitry and mechanisms will be of benefit not only to improving function after a spinal cord injury but also to developing therapies for other neurological diseases and conditions.

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Spinal Cord Injury: Progress, Promise, and Priorities TABLE ES-1 Priorities for Spinal Cord Injury Research Develop neuroprotection therapies: identify interventions that promote neuroprotective mechanisms that preserve the spinal cord. Promote axonal sprouting and growth: enhance understanding of the molecular mechanisms that promote and inhibit axonal regeneration—including the roles of glia (astrocytes and oligodendrocytes), scar formation, and inflammation and inhibitory molecules—and develop therapeutic approaches to promote growth. Steer axonal growth: determine the molecular mechanisms that direct axons to their appropriate targets and regulate the formation and maintenance of appropriate synaptic connections. Reestablish essential neuronal and glial circuitry: advance the understanding of the molecular mechanisms that regulate the formation and maintenance of the intricate neuronal and glial circuitry, which controls the complex multimodal function of the spinal cord, including autonomic, sensory, and motor functions. Increase knowledge of the mechanisms that control locomotion, including the differences in the central pattern generator between bipeds and quadrupeds. Prevent acute and chronic complications: develop interventions that prevent and reverse the evolution of events that lead to the wide range of outcomes that result from chronic injury and disability after a spinal cord injury. Maintain maximal potential for recovery: expand the understanding of the requirements for proper postinjury care and rehabilitation that are needed to maintain the maximal potential for full recovery. Recommendation 5.1:1 Increase Efforts to Develop Therapeutic Interventions The National Institutes of Health, other federal and state agencies, nonprofit organizations, and the pharmaceutical and medical device industries should increase research funding and efforts to develop therapeutic interventions that will prevent or reverse the physiological events that lead to chronic disability and interventions that are applicable to chronic spinal cord injuries. Specifically, research is needed to improve understanding of the basic mechanisms and identify suitable targets to promote neuroprotection, foster axonal growth, enhance axonal guidance, regulate the maintenance of appropriate synaptic connections, and reestablish functional neuronal and glial circuitry; and 1   For ease of reference, the committee’s recommendations are numbered according to the chapter of the main text in which they appear followed by the order in which they appear in the chapter.

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Spinal Cord Injury: Progress, Promise, and Priorities enhance understanding of proper postinjury care and rehabilitation, such as retraining, relearning, and the use of neuroprostheses, to create the groundwork required to maintain and enhance the maximal potential for full recovery. Recommendation 5.2: Develop a Strategic Plan for Combination Therapeutic Approaches The National Institute of Neurological Disorders and Stroke should develop a strategic plan to screen and assess the potential for compounds and therapies to be used in combination to treat acute and chronic spinal cord injuries. BOLSTERING THE RESEARCH INFRASTRUCTURE Progress in spinal cord injury research depends on adequate research funding and an adequate physical infrastructure for research; well-trained and innovative investigators with career development opportunities; translational efforts that move the findings of preclinical studies to clinical trials with humans, as safe and appropriate; and an environment that promotes and encourages interdisciplinary collaboration. Foundations and other nonprofit organizations, state and federal governments, academic institutions, and others are attempting to fund and conduct research on spinal cord injuries. The National Institute of Neurological Disorders and Stroke supports an extensive extramural research program in spinal cord injuries and should continue to devote resources to both extramural and intramural research programs to build on these efforts. The pressing issue is how best to improve the current organization of basic and clinical research—the research infrastructure—to nurture and accelerate progress. Key to accelerating progress in the treatment of spinal cord injuries is the development of a coordinated, focused, and centralized network that connects individual investigators, research programs, and research centers; facilitates collaborative and replicative research projects; incorporates relevant research from diverse fields; and builds on the unique strengths of each research effort to move toward effective therapies. A research network is of particular importance in spinal cord injury research because of the emphasis on interdisciplinary research and the need for an organized and systematic approach to examining potential combination therapies. This dedicated focus on translational research would be spearheaded by the Spinal Cord Injury Research Centers of Excellence (discussed below) and would involve collaborations with all sites performing research relevant to spinal cord injuries. Although online technologies greatly enhance the nearly instantaneous sharing of ideas across the nation and globally, the research

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Spinal Cord Injury: Progress, Promise, and Priorities network envisioned by the committee would involve not only a strong virtual component but also a structured plan for periodic and regular meetings and workshops to set priorities and strengthen interactions. As a basis for this network, the committee urges a strong commitment by the federal government to designate and support Spinal Cord Injury Research Centers of Excellence. This would involve the establishment of new centers of excellence and the designation of several current spinal cord injury research programs as Centers of Excellence. Several multidisciplinary spinal cord injury research centers already exist, including the Miami Project to Cure Paralysis, the Kentucky Spinal Cord Injury Research Center, the Reeve-Irvine Research Center, and research centers funded by the National Institutes of Health. The translational capacities of existing research centers should be strengthened, and two to three additional research centers of excellence should be established and sustained. Centers should be developed regionally to facilitate clinical trial networks. It is important that the centers interface not only with state research programs and nonprofit organizations but also with U.S. Department of Veterans Affairs spinal cord injury research centers as well as the Model Spinal Cord Injury Care System clinics and patient care centers to broaden the potential research base for clinical trials. A national effort to prioritize translational research on spinal cord injuries would expand the capacity to explore and develop therapeutic approaches. Spinal cord injury is a multidisciplinary problem, and thus, spinal cord injury research requires collaborations among scientists and clinicians with diverse backgrounds. Therefore, a key component of the proposed Spinal Cord Injury Research Centers of Excellence should be the capacity to provide an environment that encourages comprehensive interdisciplinary research. The centers should bring together and support investigators from multiple fields, including, but not limited to, neuroscience, cellular and molecular biology, systems biology, immunology, engineering, bioengineering, biostatistics, epidemiology, and clinical medicine. Recommendation 7.2: Establish Spinal Cord Injury Research Centers of Excellence The National Institutes of Health should designate and support five to seven Spinal Cord Injury Research Centers of Excellence with adequate resources to sustain multidisciplinary basic, translational, and clinical research on spinal cord injuries. This would involve establishing two to three new Centers of Excellence and designating three to four current spinal cord injury research programs as Centers of Excellence.

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Spinal Cord Injury: Progress, Promise, and Priorities Recommendation 7.3: Establish a National Spinal Cord Injury Research Network The National Institutes of Health should be appropriately funded to establish a National Spinal Cord Injury Research Network that would coordinate and support the work of an expanded cadre of researchers. STRENGTHENING NEW YORK STATE’S RESEARCH PROGRAM Currently, 14 states have enacted legislation to fund spinal cord injury research at an annual total level of funding of about $27 million. Many of the states that fund spinal cord injury research do so through surcharges on fines for traffic violations. Some state programs provide funding to specific academic institutions to conduct research, and other states have developed or have contributed to funding extensive spinal cord research centers in their states. There is much that the states can learn from one another in developing and strengthening their spinal cord injury research programs. In 1998, New York State passed legislation to establish a new program whose ambitious mission is to support research “towards a cure for [spinal cord] injuries and their effects.” Funding for the program comes from a surcharge on traffic violations, which is directed to the newly created Spinal Cord Injury Research Trust Fund. The estimated annual funding of $8.5 million is the largest amount of state-designated funding for spinal cord injury research. Its size and scope place the program in the position to become a leader in spinal cord injury research. Furthermore, New York has a strong biomedical and neuroscience research infrastructure that could be drawn upon to build a strong research program in spinal cord injuries. The program possesses several features that bode well for future progress, including a sophisticated grant review structure (two tiered) and scientific board, a strong translational component, multiple types of grants, and an expansion capacity that could be realized by drawing on the unique strengths of New York State’s biomedical research and clinical research programs. Opportunities to strengthen New York State’s program, to reduce the administrative bureaucracy, and to bolster its impact also exist. The committee’s recommendations focus on the following four areas: building and strengthening New York State’s research infrastructure, developing a regional clinical trials center, restructuring the research funding and oversight processes, and ensuring independent evaluation of the progress that has been made toward the stated mission of the New York State Spinal Cord Injury Research Board.

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Spinal Cord Injury: Progress, Promise, and Priorities ACCELERATING PROGRESS Progress in spinal cord injury research offers the potential to make significant improvements in the lives of individuals with spinal cord injuries. The challenges are to move research efforts forward in such a way as to accelerate the translation of the findings from research in the laboratory to clinical trials and then into clinical practice while ensuring patient safety and effectiveness. Although few therapeutic interventions are ready for clinical trials, the body of knowledge on the mechanisms underlying neuronal injury and repair is increasing rapidly, and many potential therapies show promise in in vitro studies and in studies with animals. The committee believes that accelerating progress in spinal cord injury research involves the following three key efforts that, in addition to the recommendations for the New York State program, are the focus of the committee’s recommendations (Box ES-1) and highlight the need for a concerted national priority effort to find the best treatments for spinal cord injuries. Focus on increasing knowledge of basic neurobiology and therapeutic approaches. Many research avenues remain to be examined in understanding the biochemical mechanisms responsible for spinal cord injuries and thus the targets of therapeutic interventions. Research is needed on the processes involved in maintaining cellular viability and the therapeutic targets for those processes, the mechanisms that promote and inhibit axon regeneration, and the processes by which axons are directed to their appropriate targets and that regulate the formation and maintenance of appropriate and functional synaptic connections and circuitry. As no one solution for spinal cord injuries likely exists, strategies need to be developed to provide an organized approach to testing and evaluating therapies in combination. To conduct this research, new and refined technologies are needed. In addition, assessment measures need to be standardized to provide insights into potential therapeutic interventions. Efforts are needed to improve animal models and assessment techniques, increase training efforts on the use of standardized research tools and techniques, identify biomarkers that can be used to monitor the progression of injury and recovery, improve imaging technologies to provide a real-time means to assess spinal cord injuries, and standardize outcome measures for preclinical studies. Emphasize and coordinate translational multidisciplinary research and clinical trials. Research on spinal cord injuries is now at the point at which the biological targets and pathways that can be the focus of interventions can be identified. The development of regional clinical trial networks, the bolstering of collaborative efforts between basic and clinical researchers through the development of research centers, as well as the development of

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Spinal Cord Injury: Progress, Promise, and Priorities a structured and focused research network will provide the opportunities to develop safe and effective therapeutic interventions. It is important for the pharmaceutical industry to be involved in these efforts and for collaborative approaches to be developed among industry, academic, nonprofit, state, and federal resources. Furthermore, it is critically important that ongoing efforts in patient care and rehabilitation be coordinated with efforts directed toward the development of therapeutic interventions for spinal cord injuries. Strengthen the research infrastructure and enhance training. High-quality neuroscience research has resulted in significant advances in understanding neuronal injury and repair. By improving and bolstering the research infrastructure through the development of research centers of excellence and enhanced training efforts, scientists will be encouraged to collaborate in efforts to accelerate research progress. It also offers the opportunity to draw a large cadre of young basic neuroscientists into the field of spinal cord injury research. Furthermore, it is important to establish a research network that can provide the structure for collaborative initiatives and multicenter clinical trials. Strengthening the research infrastructure will attract additional top-notch researchers and their students to contribute to research on these complex issues. In acknowledging the opportunities ahead for spinal cord injury research, care must also be taken not to minimize the challenges. Treating spinal cord injury, particularly in the near term, will involve improving functional deficits and quality of life. The complexity of the nervous system, the varied nature of spinal cord injuries, and the severity of the loss of function present real and significant hurdles to be overcome to reach the ultimate goals of restoring total function. The urgent need to cure this devastating condition should not tempt overly optimistic predictions of recovery or time frames that cannot be met. Neither the scientific community nor the community of individuals with spinal cord injuries is content with the limited therapeutic options currently available for the treatment of spinal cord injuries. There is an obvious and urgent need to identify and test new interventions and to accelerate the pace of research, particularly in moving laboratory findings to clinical practice. Spinal cord injury involves serious and traumatic adverse changes to the human body, and an extensive research effort is needed to develop treatment approaches for the range of health outcomes faced by individuals with spinal cord injuries.

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Spinal Cord Injury: Progress, Promise, and Priorities BOX ES-1 Summary of the Committee’s Recommendations The following is a summary of the committee’s recommendations. Complete text of each recommendation can be found in the corresponding chapters. Focus on Increasing Knowledge of Basic Biology and Therapeutic Approaches Increase Efforts to Develop Therapeutic Interventions (Recommendation 5.1) Specifically, research is needed to: improve understanding of the basic mechanisms and identify suitable targets to promote neuroprotection, foster axonal growth, enhance axonal guidance, regulate the maintenance of appropriate synaptic connections, and reestablish functional neuronal and glial circuitry; and enhance understanding of proper postinjury care and rehabilitation, such as retraining, relearning, and the use of neuroprostheses, to create the groundwork required to maintain and enhance the maximal potential for full recovery. Develop a Strategic Plan for Combination Therapeutic Approaches (Recommendation 5.2) The National Institute of Neurological Disorders and Stroke should develop a strategic plan to screen and assess the potential for compounds and therapies to be used in combination to treat acute and chronic spinal cord injuries. Bolster and Coordinate Research on Neuronal Injury and Repair (Recommendation 7.1) The National Institutes of Health should increase the funding for mechanisms that encourage research coordination in neuronal injury and repair and should actively develop and support cross-institute and cross-disciplinary working groups, as outlined in the NIH Blueprint for Neuroscience Research. Improve and Standardize Research Tools and Assessment Techniques (Recommendation 3.2) Preclinical research tools and animal models should be developed and refined to examine spinal cord injury progression and repair and assess the effectiveness of therapeutic interventions. These preclinical tools and assessment protocols should be standardized for each type and each stage of spinal cord injury. Increase Training Efforts on Standardized Research Tools and Techniques (Recommendation 3.1) Spinal cord injury researchers should receive training in the use of standardized animal models and evaluation techniques.

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Spinal Cord Injury: Progress, Promise, and Priorities Emphasize and Coordinate Translational Multidisciplinary Research and Clinical Trials Facilitate Clinical Trials (Recommendation 6.1) Mechanisms should be implemented that will facilitate the implementation of clinical trials while observing the established standards for the protection of human subjects in clinical research, including: coordinating existing facilities and resources in acute care, chronic care, and rehabilitation to support multicenter clinical trials, utilizing central institutional review board mechanisms, coordinating and expanding patient registries and databases to improve mechanisms to conduct clinical trials and facilitate patient recruitment, developing a set of standardized clinical outcome measures, and designing clinical trials that are a multidisciplinary effort and should incorporate, as appropriate, small “n” methodologies for early-phase clinical trials. Increase Industry Involvement (Recommendation 6.2) Mechanisms should be explored that can be used to link federal, state, academic, and nonprofit efforts with those of industry with the goal of increasing the investment and involvement of the private sector in the development of therapeutic interventions for spinal cord injuries. Strengthen the Research Infrastructure and Enhance Training Establish Spinal Cord Injury Research Centers of Excellence (Recommendation 7.2) The National Institutes of Health should designate and support five to seven Spinal Cord Injury Research Centers of Excellence with adequate resources to sustain multidisciplinary basic, translational, and clinical research on spinal cord injuries. Establish a National Spinal Cord Injury Research Network (Recommendation 7.3) The National Institutes of Health should be appropriately funded to establish a National Spinal Cord Injury Research Network that would coordinate and support the work of an expanded cadre of researchers. Increase Training and Career Development Opportunities (Recommendation 7.4) Resources should be designated to strengthen education programs for pre-and postdoctoral training in spinal cord injury research. The National Institutes of Health Office of Science Education and the National Institute of Neurological Disorders and Stroke should enhance training and develop a training module on the functional complexity of the spinal cord for neuroscience Ph.D. and medical students.

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Spinal Cord Injury: Progress, Promise, and Priorities The National Institutes of Health, state programs, and other research organizations should increase funding for training and career development opportunities for graduate and postdoctoral researchers interested in spinal cord injury research. Strengthen New York State’s Spinal Cord Injury Research Program Build and Strengthen New York State’s Research Infrastructure (Recommendation 8.1) The New York State Spinal Cord Injury Research Board should increase its research infrastructure to meet the program’s mission. The Board should: develop and sustain a vigorous recruitment and training effort for fundamental and translational research; establish a coordinated statewide research network; cultivate formal linkages with researchers, programs, and biopharmaceutical companies in the region to forge partnerships for basic, translational, and clinical research; and establish regional core laboratory facilities. Develop a Regional Clinical Trials Center (Recommendation 8.2) The state of New York should use its unique strengths to establish a regional clinical trials center. This center should: develop and coordinate multicenter clinical trials to examine therapies for the treatment of spinal cord injuries; sponsor a clinical trial of decompression as an early intervention and clinical trials of other therapies to be used during the acute phase of a spinal cord injury by using the special opportunities offered by New York City’s geographic location and the unique resources of its trauma centers; and manage a clinical trials clearinghouse. Restructure Research Funding and Oversight Processes (Recommendation 8.3) The New York State Spinal Cord Injury Research Board should work with the state of New York to reduce administrative burdens, improve the approval and grant distribution processes, and establish a rapid-response funding mechanism to capitalize on new research ideas. Ensure Independent Evaluation (Recommendation 8.4) The New York State Spinal Cord Injury Research Board should establish an independent external review panel that meets periodically to rigorously assess the program’s efforts toward its stated mission to cure spinal cord injuries.