Spinal cord research

There are no definitive treatments yet for spinal cord injury. However, ongoing research to test new therapies is progressing rapidly. Drugs to limit injury progression, decompression surgery, nerve cell transplantation and nerve regeneration, as well as nerve rejuvenation therapies, are being examined as potential ways to minimize the effects of spinal cord injury.

The biology of the injured spinal cord is enormously complex but clinical trials are underway with more coming; hope for restoring function after paralysis continues to rise, and for good reason.

Still, paralysis from disease, stroke or trauma is considered one of the toughest of medical problems. In fact, just over a generation ago, any damage to the brain and spinal cord that severely limited motor and/or sensory function was thought to be untreatable.

In recent years, though, the word "cure" in this context has not only entered the vocabulary of the science community but also that of clinicians. Restorative neuroscience is bubbling with energy and expectation.

To be sure, scientific progress is a slow but steady march. One day in the not-too-distant future there will be a host of some procedures or treatments to mitigate the effects of paralysis. But it is not reasonable to expect a one-size-fits-all "magic bullet" for restoring function. It is almost a certainty that these coming treatments will involve combinations of therapies, given at various time points in the injury process, including a significant rehab component.

Below is a snapshot of work being done in several research areas.

Nerve protection

As in the case of brain trauma or stroke, the initial damage to spinal cord cells is followed by a series of biochemical events that often knock out other nerve cells in the area of the injury. This secondary process can be modified, thus saving many cells from damage.

The steroid drug methylprednisolone (MP) was FDA-approved in 1990 as a treatment for acute SCI and it remains the only approved acute treatment. MP is believed to reduce inflammation if people get the drug within eight hours of injury. The medical community is not entirely sold on the effectiveness of MP, and many neurosurgeons won't recommend it and suggest the steroid dosage actually causes more damage.

Meanwhile, research is underway in many labs around the world to find a better acute treatment. Several drugs look promising, including:

  • Riluzole: Protects nerves from further damage from excess glutamate.
  • Cethrin: Reduces the growth of inhibitors
  • Anti-Nogo: A molecule that promotes spinal cord cell growth by blocking inhibition.
  • AC105: Proved to be an effective neuroprotective in animal studies and improved motor function in SCI and cognitive function in TBI when initiated within four hours of injury.
  • Cooling of the spinal cord is another possible acute therapy; hypothermia appears to reduce cell loss.
  • Stem cells have also been considered as an acute therapy.

Over a century ago, Spanish scientist Santiago Ramón y Cajal noted that the ends of axons broken by trauma become swollen into what he called "dystrophic endballs" and are no longer capable of regeneration.

This remained a central issue in recovery of function – there seems to be some sort of barrier or scar that traps the nerve tips in place. Recent studies in several labs have revealed that these dystrophic growth cones can get unstuck using the molecule chondroitinase (nicknamed chase) that breaks down the sugar chains forming the scar.

There has been much work published about the potential for chase; it has helped restore function in paralyzed animals. There have been no human trials yet; effective delivery of chondroitinase to the injury site has not been fully worked out.

Bridging

The idea of a bridge is conceptually easy – transplanted cells or perhaps a type of miniature scaffold, fill the damaged area of the cord, and thus allow nerves of the spinal cord to cross through otherwise inhospitable terrain.

In 1981, Canadian scientist Albert Aguayo showed that spinal cord axons could grow long distances using a bridge made of peripheral nerve, proving without doubt that axons will grow if they have the right environment.

A variety of techniques has evolved through experiments to create a growth-enhancing environment, including the use of stem cells, nerve cells called olfactory ensheathing glia (OEG) that come from the upper nose, and Schwann cells.

Another type of bridge, or perhaps more like a bypass, stitches a piece of peripheral nerve above and below the area of spinal cord lesion. This type of surgery is not used clinically in the United States. In experiments, however, a nerve bypass restored some diaphragm function and breathing in animals with high cervical injuries, and some bladder control in animals with lower injuries. The research team is hopeful this can one day benefit people.

Cell replacement

While it may be tantalizing to think broken or lost spinal cord nerve cells can be replaced by new ones, this has yet to be done. Cell replacement is not yet a source of spare parts.

Stem cells from one's own body or from other sources have been used experimentally to restore function after paralysis. Results have been encouraging but not because the new cells take on the identity of the lost or damaged ones. Replacements seem to offer support and help nurture surviving cells.

Be mindful that stem cell therapy is considered a drug by the FDA, and the only approved use in the United States is bone marrow transplantation.

The first-ever embryonic stem cell trial was halted midstream in 2011 by its sponsor, Geron, citing financial priorities. The group hoped to use transplanted stem cells to rejuvenate existing cells in the area of an acute spinal cord injury, thereby restoring the myelin wrapping necessary for signal transmission.

Five people were enrolled in the Phase I trial, looking mainly at safety. There were no adverse effects reported, but no functional gains either. The Geron cells may get a reprise, as two former Geron executives acquired the rights to the cell line and formed a new company, BioTime, intending to run more trials.

In an ongoing clinical trial in Switzerland, StemCells, Inc., is testing human stem cells from a fetal source in people injured three months to a year. These cells are also believed to restore myelin. The first trial is showing the cells are safe and early data indicates some return of sensory function, too.

The science behind the StemCells, Inc. trial comes from the labs of husband-and-wife team Brian Cummings and Aileen Anderson at the University of California, Irvine. Anderson is a member of the Reeve International Research Consortium on Spinal Cord Injury. StemCells, Inc. has begun preclinical animal studies in hopes of developing a potential treatment for long-term cervical spinal cord injury.

A third SCI stem cell clinical trial, underway from a company called Neuralstem, is testing human neural cells in chronic SCI, one-to two-years post-injury. The transplanted cells are derived from stem cells native to the brain and spinal cord. The company found a way to produce them in large quantity for direct injection to the spinal cord, which is actually same cell line has been in clinical trials for several years for ALS.

In preclinical studies using Neuralstem's human cells in animals, researchers suggest the replacement cells integrate with spinal nerves and form new relay circuits. The animals showed significantly improved function.

This preliminary success with animals might have to do with the delivery system, using a fibrin matrix as a scaffold, plus the addition of a cocktail of growth factors. The first human trials, however, won't test the combination of matrix or factors.

Clinical trials in several countries have tested the safety and efficacy of OEG cells transplanted into the lesion area of the spinal cord and results have been promising.

Meanwhile, the Miami Project has begun a clinical trial for transplanted Schwann cells, support cells of peripheral nerves that have been shown to encourage the regrowth of axons after spinal cord injury.

Combining Schwann cells with other growth molecules may ultimately be more useful than transplants of Schwann cells alone. For example, a team at the Miami Project found that Schwann cells alone activated nerves to grow into a bridge but they stopped short of crossing the gap in the injured spinal cord. By adding OEG cells to the Schwann cells, the axons crossed the bridge and entered the spinal cord on the other side of the lesion.

Regeneration

This is perhaps the toughest of the treatment possibilities. To restore a major degree of sensation and motor control after spinal cord injury, long axons must grow again and connect over long distances – as much as two feet – to precise targets.

These axons cannot regenerate unless their path is cleared of poisons, enriched with vitamins, and paved with an attractive roadbed. By blocking inhibitory factors (proteins that stop axon growth in its tracks), adding nutrients, and supplying a matrix to grow on, researchers have indeed grown spinal nerves over long distances.

One group of scientists at several labs used a molecular switch to turn on nerve cell growth after trauma. PTEN is a tumor suppressor gene that was discovered by cancer researchers fifteen years ago. This gene regulates cell growth and it turns out to be a molecular switch for axon growth.

When scientists deleted PTEN in a complete spinal cord injury model, cortical spinal axons – the ones needed for major movement function – regenerated at unprecedented rates.

PTEN is complicated. You can't just get rid of it because it is the brake needed to stop certain kinds of cellular overgrowth (cancer), but there are ways to release it. Much work remains to make this relevant to human spinal cord injuries, but many more labs are exploring the PTEN gene and many others related to regrowth of nerve cells.

Rehabilitation

Almost any treatment to restore function after paralysis will require a physical component to rebuild muscle, build bone, and reactivate patterns of movement. Some form of rehab will be needed after function comes back. Moreover, it appears that activity itself affects recovery.

In 2002, seven years after his supposedly complete C2 injury, Christopher Reeve showed that he had regained limited function and sensation. His doctor credited his use of functional electrical stimulation (FES), which may have kick-started the repair process, and a program of passive electrical stimulation, aqua therapy, and passive standing.

To a limited extent, Christopher also used treadmill training, a type of physical therapy that forces the legs to move in a pattern of walking as the body is suspended in a harness above a moving treadmill.

The theory is that the spinal cord can interpret incoming sensory signals; the cord itself is smart. It can carry out movement commands without brain input.

Locomotion is managed by a system called a central pattern generator (CPG), which activates the pattern of stepping. Stepping during treadmill training sends sensory information to the CPG, reminding the spinal cord how to step.

Scientists describe the reactivation due to stepping as plasticity – the nervous system is not "hard wired" and appears to have the ability to adapt itself to new stimulation. Researchers are learning much more about the CPG and how to activate it.

Rehabilitation techniques have evolved to the point that exercise and physical activity are an essential component of recovery. For the person with a spinal cord injury, it's best to stay active and always strive for the maximum outcome.

Source: American Association of Neurological Surgeons, Craig Hospital, Christopher & Dana Reeve Foundation, The National Institute of Neurological Disorders and Stroke