By Wise Young, M.D., Ph.D.
The year 2000 has been a heady time for spinal cord injury research. Over 600 spinal cord injury studies were published during the first half of the year. I will focus on six promising therapies of spinal cord injury: Nogo inhibitors, therapeutic vaccines, stem cells, olfactory ensheathing glia, neurotrophins and inosine. Although several of these therapies have been reported earlier, significant advances were made during the past six months that have brought these therapies closer to clinical trial.
In 1988, Martin Schwab and his colleagues at the University of Zurich discovered that a protein in the spinal cord inhibited axonal growth and that an antibody called IN-1 allowed regeneration in the spinal cord. This discovery overturned the long-held dogma that the spinal cord cannot regenerate, but the group could not make a satisfactory form of IN-1 that could be given to humans.
In January 2000, they identified and characterized the gene for the growth-inhibiting protein called Nogo. The discovery of the Nogo gene has provided exciting new tools to develop IN-1 analogs for human.
Why apply antibodies against Nogo when you can induce the body to make its own antibodies against growth inhibitors in the cord? Sam David and his colleagues at the Montreal Institute of Neurology simply inoculated mice with spinal cord extracts three weeks before spinal cord transection. Half of the vaccinated mice remarkably regenerated their spinal cords and recovered walking. In some of the mice, over 75 percent of the transected axons regrew across the injury site.
Stem Cell Transplants
The central nervous system contains stem cells that can produce neurons, astrocytes and oligodendroglia. John McDonald and his colleagues at the University of Washington transplanted embryonic stem cells into a contused rat spinal cord. Implanted nine days after injury, the stem cells survived, differentiated and improved locomotor recovery in the rats. This is the first demonstration that stem cell transplants improve recovery after spinal cord injury.
Olfactory Ensheathing Glia
These unusual cells are responsible for the regenerative ability of the olfactory nerve. Several groups have reported that OEG transplants facilitate axonal regeneration after partial spinal cord lesions. Almuenda Ramon-Cueto and her colleagues in Madrid recently reported that OEG transplants induced regeneration and locomotor recovery of rats with transected spinal cords.
The brain and spinal cord make growth factors that stimulate neuronal growth and survival. Called neurotrophins, these factors can work alone or in combination with IN-1 and cell transplants to facilitate spinal cord regeneration and recovery. Marie Filbin and her colleagues at Hunter College of the City University of New York recently showed that neurotrophins allowed axons to ignore growth inhibitors.
Larry Benowitz and his colleagues at the Harvard Medical School recently reported that inosine, a purine nucleotide, strongly stimulates axonal growth in the spinal cord. Applied to the brain after spinal cord hemisection, inosine represents a new therapeutic approach: the use of small messenger molecules to stimulate neuronal growth.
Much work still needs to be done to show that these therapies work in chronic spinal cord injury, to optimize the therapies (alone or in combination) and to develop practical delivery approaches for human. However, all of these therapies have strong potential to help humans with chronic spinal cord injury.
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