Shaping the future of SCI research

Over the years, members of the International Research Consortium on Spinal Cord Injury have made key discoveries that have led directly to potential spinal repair treatments. Several of these are entering or close to clinical trials with the findings from Consortium researchers as the foundation of each advance.

The Consortium mirrors Christopher Reeve’s vision of a “laboratory without walls” by uniting some of the brightest experts in the field and creating a collaborative environment to share insights and learnings.

Christopher Reeve knew that innovation and scientific discovery could not flourish in a vacuum.

By bringing together experts from different disciplines, the seven Consortium laboratories have accelerated the Reeve Foundation mission and helped shape the future of the field. Below are a few examples of how their work has resulted in promising discoveries.

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 initial demonstration that blocking NogoA with an antibody could promote regeneration.

There have since been experiments in several laboratories indicating that NogoA-related interventions can promote spinal cord repair. Novartis conducted a Phase I safety study of the Schwab anti-NogoA antibody and based on those results, Dr. Schwab and colleagues are exploring a larger Phase II clinical trial.

Epidural stimulation and Locomotor Training

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 (communication between neurons) and therapies like Locomotor Training could enable stepping, even years after a complete transection.

A few years ago, the Edgerton team combined these therapies with epidural stimulation in rodents with complete injuries, demonstrating significant improvements in stepping.

These early discoveries formed the basis of the Reeve Foundation’s NeuroRecovery Network® and more recent findings are the basis for Reeve-supported studies on epidural stimulation and rehabilitation that are ongoing now for people with complete spinal cord injury.

Stem cell transplants

Several years ago in a series of animal experiments, the Anderson laboratory characterized the behavior of a proprietary line of human neural stem cells (HuCNS-SCs), including the method of transplantation and their therapeutic window.

Now, based on the results of Dr. Anderson’s Phase I/II clinical trial, StemCells Inc. is conducting a Phase II proof of concept trial using HuCNS-SC in cervical spinal cord injury. In this study, research participants are being treated between 10 to 23 months post-injury.

Chondroitinase

The effectiveness of chondroitinase for central nervous system (CNS) repair was first demonstrated by the Fawcett laboratory and has since been repeated in several other laboratories. Injured axons or nerve fibers in the spinal cord try to initiate a regenerative response following an injury. They are stuck, however, in a thick scar tissue caused by the trauma to the spinal cord, sealing off the area.

Chondroitinase, an enzyme which is derived from toxic bacteria, can be applied to dissolve the scar tissue.

The potential of chondroitinase to enhance the effect of rehabilitation was also shown in the Fawcett laboratory. Chondroitinase is currently in preclinical development with Acorda Therapeutics.

Consortium laboratories have made leading fundamental contributions on the inhibitory CNS environment, including 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 within the individual laboratories and from a large number of inter-lab collaborations across the Consortium.

Identifying and regenerating specific spinal circuits

Recovery from spinal injury requires a reconstruction of the spinal cord circuits. Within the cord there are specialized circuits responsible for different types of movement, sensation and autonomic control. Our knowledge of these circuits is very incomplete, mainly because we have lacked markers to identify the 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.

We currently rely on the 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, which has identified neurons that receive connections from the corticospinal tract, together with the discovery of genetic markers that can be visualized in adult mice and can identify these neurons.

The Consortium now has the possibility to link particular neuronal types to specific behaviors or physiological patterns and reflexes, as well as determine the patterns of connections to and from specific neuronal types. With this knowledge our hope is to engineer neuronal types to attract regenerating neurites and target specific neurons, thus restoring selected behaviors.

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 to create new connections and remove regressing connections. Astrocytes also participate in perineuronal nets, a target of the enzyme chondroitinase and a key controller of plasticity.

Microglia, through direct action or through secretion of a 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 further examination in spinal injury to develop new therapeutic tools.