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Combination Therapy Stimulates Spinal Cord Regeneration in Rats More Than One Year after Injury

For release: Monday, February 1, 2010

In a study on animals, researchers found that a combination of treatments can stimulate the growth of severed axons (nerve fibers) across an injured spinal cord, even when the treatments are delayed for more than a year.

The study is significant because it is one of only a few studies that have shown that nerve cells can be stimulated to regenerate long after an injury, and offers hope for people living with chronic spinal cord injury, says Naomi Kleitman, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS).  Most studies of spinal cord injury have focused on acute treatments, given within hours to days of the injury.

“A year is nearly a third of the lifespan of the rodents that were tested, so this is one of the best demonstrations of successful growth in chronic injuries we’ve seen,” Dr. Kleitman says.

Several factors make it difficult to recover from injury to the spinal cord.  Although the developing spinal cord contains signals that encourage nerve cells to grow, by adulthood those have been replaced by signals that inhibit growth and maintain stable connections.  Changes within nerve cells themselves also direct them to stop growing as they mature.

The new research, led by Mark Tuszynski, M.D., Ph.D., of the University of California San Diego, focused on a rat model of spinal cord injury that involves damage to sensory nerve cells.  (These cells have one branch that projects through the spinal cord to the brain, and another branch that travels through a peripheral nerve and transmits sensory information from the body’s extremities.)

Dr. Tuszynski and postdoctoral fellow Ken Kadoya, M.D., Ph.D., and their team have developed a three-part strategy to stimulate regrowth in this model of spinal cord injury.  It involves using a graft of bone marrow cells to support growth of the damaged sensory axons across the injury, and an injection of a growth factor called neurotrophin-3 (NT-3) to attract the axons toward the brain.  The growth is also stimulated by a “conditioning lesion” to the peripheral nerve, which is believed to re-activate the sensory nerve cells’ dormant growth and repair genes.

In August 2009, Dr. Tuszynski and his team reported that, applied acutely after spinal cord injury, this combination therapy can stimulate sensory axons to regrow robustly and reconnect with target areas in the brain.

In a more recent study published in Neuron,* the team tested the combination therapy on rats at six weeks post-injury and 15 months post-injury.  More than 60 percent of the treated rats showed evidence of axon bridging across the lesion when the combination therapy was given at six weeks.  Remarkably, about 45 percent of rats showed evidence of axon bridging when the therapy was delayed until 15 months.  In all cases, there was substantially less axon growth if any part of the combination therapy was omitted.

This study did not test functional recovery.  Earlier studies from the group testing combination treatments after acute spinal cord injury showed that spinal sensory axons regenerating into an appropriate target in the brain did not restore function, in part because the regenerating axons were not covered in myelin, an insulating material that speeds nerve impulses.  The researchers are investigating whether the addition of myelin-forming cells to the treatment regimen can produce functional recovery, Dr. Tuszynski says.

In a separate set of experiments, Dr. Tuszynski and his team took a closer look at the effect of the conditioning lesion to the peripheral nerve, to test the theory that it stimulates nerve cells to engage their internal repair programs.  They found that “conditioning lesions” jumpstart potentially thousands of genes, including two that are known to become active in nerve cells during axon growth.  (Another recent study used a unique screening method to identify a family of genes that regulates axonal growth programs.)

“To devise a therapeutic strategy that is safe for patients, we have to find a better way to turn on the axon regeneration programs without causing further injury to the nerve cells,” notes Dr. Kleitman.  By identifying genes involved in axon regeneration, researchers may be able to develop drugs or small molecules to target them, she says.

-By Daniel Stimson, Ph.D.

*Kadoya, K et al.  “Combined Intrinsic and Extrinsic Neuronal Mechanisms Facilitate Bridging Axonal Regeneration One Year After Spinal Cord Injury.”  Neuron, October 29, 2009, Vol. 64, pp. 165-172.

Last Modified May 30, 2012