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Research

International Research Consortium on Spinal Cord Injury

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Over the years, Consortium members have made some of the key discoveries that have led directly to potential spinal repair treatments. Four such interventions for recovery of function after spinal cord injury are currently in trials or near to trials. Discoveries by Consortium laboratories have been the foundation of each of these advances.

Anti-NogoA
The identification of NogoA as the major inhibitory molecule on myelin was achieved by the Schwab laboratory. The first anti-NogoA antibody was produced by Schwab and his colleagues, together with the first demonstration that blocking NogoA with an antibody could promote regeneration. There have since been experiments in several laboratories showing that NogoA-related interventions can promote spinal cord repair. The Schwab laboratory produced the anti-NogoA antibody that is currently in clinical trials with Novartis.

Epidural Stimulation
The Edgerton laboratory has worked for many years on methods to promote stepping after spinal cord injury, demonstrating that the combination of drugs affecting synaptic transmission and Locomotor Training could enable stepping, even after complete transection. A few years ago the laboratory combined these drug treatments and training with epidural stimulation, showing that dramatic improvements in stepping and recovery of some autonomic function could be achieved. These discoveries formed the basis of the Foundation’s NeuroRecovery Network and the very promising studies of epidural stimulation with rehabilitation that are ongoing now in patients with complete spinal cord injury.

Stem Cell Transplants
A Phase I/II clinical trial is now underway at Balgrist Hospital, Zurich of StemCells Inc.’s human neural stem cells (hNSCs) in chronic spinal cord injury. The research on these cells in animal models of spinal cord injury was performed by the Anderson laboratory in a series of experiments that characterized the behavior of these cells, the method of transplantation and the therapeutic window.

Chondroitinase
The efficacy of the enzyme chondroitinase for CNS repair was first shown by the Fawcett laboratory, and has since been repeated in numerous other laboratories. The ability of chondroitinase to enhance the effect of rehabilitation was also shown in the Fawcett laboratory. Chondroitinase is in preclinical development with Acorda Therapeutics.

Consortium laboratories have made leading fundamental contributions on the inhibitory CNS environment, injury responses, mechanisms of axon regeneration, neural stem cell biology, spinal cord circuitry, physiology, mechanisms of rehabilitation, neural development, synaptogenesis and synaptic pruning, injury responses, glial behavior and other areas. These have come both from the programs in the individual laboratories and from a large number of Consortium inter-lab collaborations.

Over the next funding cycle, Consortium projects will fall into the following priority areas:

Identifying and regenerating specific spinal circuits
Recovery from spinal injury requires reconstruction of spinal cord circuits. Within the cord there are specialized circuits responsible for different types of movement, for sensation and for autonomic control. Our knowledge of these circuits is very incomplete, mainly because we have lacked markers to allow us to identify the different types of spinal cord neurons that form these circuits. We can see regenerated axons and axon sprouts making new connections after injury, but we do not have a way of knowing which types of neurons they are connecting to. At present, therefore, we have to rely on the apparently random growth and sprouting of axons that occurs after injury, hoping that useful circuitry will arise. But new opportunities are emerging to identify types of neurons and circuits in the cord, opening the possibility that we will be able to achieve targeted reconstruction of particular circuits. The new opportunity arises from work within the Pfaff laboratory that has identified neurons that receive connections from the corticospinal tract, together with the discovery of genetic markers that can be visualized in adult mice, which identify these neurons. The Consortium therefore has the possibility to link particular neuronal types to particular behaviors, particular neuronal types to particular physiological patterns and reflexes, and work out the patterns of connections to and from particular neuronal types. With this knowledge it should be possible to engineer neuronal types to attract regenerating neurites or particular projection neurons to target specific neurons, thus restoring selected behaviors.

Building on the success of epidural stimulation
The finding by the Edgerton laboratory that combining rehabilitation with epidural stimulation can lead to excellent restoration of function has led to the highly successful early translation of this intervention into several complete ASIA A or B spinal patients. At present our knowledge of how epidural stimulation works is fairly basic and the expectation is that further refinement of the method could lead to further clinical benefits. At present the research has focused on hind limb walking. Consortium projects will expand that work to include forelimb motor function, and to investigate the control of neuropathic pain through modulation of thalamic inputs.

Control of adaptive and maladaptive plasticity by astrocytes and microglia
Restoration of function through the modulation of plasticity is a key Consortium objective. Recent work from the Barres laboratory and elsewhere has shown the key role played by astrocytes and astrocyte-secreted molecules in the formation of new connections and in removal of regressing connections. Astrocytes also participate in perineuronal nets, a target of chondroitinase and a key controller of plasticity. Equally, microglia through direct action or through secretion of complement pathway molecules, are important in the removal of connections. Through microglia, inflammation can influence regeneration and plasticity. We now have a new level of understanding of how connections can be made and broken. However much of the work comes from in vitro experiments, and the concepts are ripe for examination in spinal injury and other in vivo models, and for targeting to create new therapeutic tools.

CHRISTOPHER AND DANA REEVE FOUNDATION
INTERNATIONAL RESEARCH CONSORTIUM ON SPINAL CORD INJURY

   
Aileen Anderson, MD, Ph.D. Aileen Anderson, Ph.D.,
University of California, Irvine, California
   
Ben Barres, MD, Ph.D. Ben Barres, MD, Ph.D.,
Stanford University, Stanford, California
   
V. Reggie Edgerton, Ph.D. V. Reggie Edgerton, Ph.D.,
University of California, Los Angeles, CA
   
James W. Fawcett, Ph.D. James W. Fawcett, Ph.D.,
University of Cambridge, Cambridge, UK
   
Lorne M. Mendell, Ph.D. Lorne M. Mendell, Ph.D.,
State University of New York, Stony Brook, NY
   
Samuel L. Pfaff, Ph.D. Samuel L. Pfaff, Ph.D.,
The Salk Institute, La Jolla, CA
   
Martin E. Schwab, Ph.D. Martin E. Schwab, Ph.D.,
University of Zurich, Zurich, Switzerland

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Continue Christopher Reeve's LegacyPhoto by Timothy Greenfield-Sanders