Combination Strategy Promotes Better Recovery of Walking

Investigators at The Miami Project have designed a new triple combination strategy that opens up new possibilities in the search for successful treatments for spinal cord injury. Damien D. Pearse, Ph.D., working with Mary Bartlett Bunge, Ph.D. and colleagues, tested their new strategy and found the treated animals improved to 70% of normal walking function. The new treatment combines Schwann cell grafts with the administration of rolipram and a form of cyclic AMP, drugs that influence Axon growth.

Previous studies pioneered at The Miami Project have shown that Schwann cell transplants by themselves support Regeneration in experimental spinal cord injury. What these earlier studies with Schwann cell grafts did not do is promote axons to leave the grafts and extend beyond the site of injury.

Researchers have learned that a reason the fibers do not re-enter the spinal cord beyond Schwann cell grafts is likely because of an inhibitory Environment that exists within the spinal cord. These observations led Pearse and Bunge to consider a combination strategy to help damaged neurons overcome inhibitory signals after injury.

Research colleague Marie Filbin, Ph.D. of Hunter College, New York, recently demonstrated that cyclic adenosine monophosphate (cAMP), a messenger molecule that influences the inner workings of cells, is important for growth of axons across inhibitory environments. Interested in knowing what happens to cAMP after injury, Pearse and Bunge’s team determined the levels of cAMP in the brain and spinal cord following a contusion injury. They found that the levels of cAMP drop well below normal within one day of injury.

The Combination
To help counteract the drop in levels of cAMP after injury, Pearse and Bunge administered rolipram (panel A) at the time of injury. Rolipram is a drug that prevents the initial decrease in cAMP. This drug’s safety has already been tested in humans. It is also able to travel through the blood stream and is easily administered by subcutaneous injection (under the skin.)

One week after the injury and the administration of rolipram, they transplanted Schwann Cells into the injury site (panel B). During the transplant procedure, they also injected a form of cAMP above and below the level of the spinal injury to help raise the levels of cAMP.

Significant Findings
Dr. Bunge commented, “In the 15 years that I have been at The Miami Project to Cure Paralysis, this is the most exciting and important work that has been done in my laboratory.” Her excitement comes from the dramatic improvements seen in the treated animals.

“The amount of Functional recovery reported after the combination strategy described in this paper is quite impressive,” says Naomi Kleitman, Ph.D., a program director for spinal cord injury research at NINDS, a component of the National Institutes of Health. “The report is a good example of the process by which science advances. Each of the pieces of the strategy have been hailed as ‘promising’ in earlier reports, but the behavioral effects were not huge. With the right combination, the sum is now proving to be much greater than the parts.”

Possible reasons for the enhanced walking may be explained by other significant findings from the study. The combination treatment had an effect on neurons in the brain by promoting growth of their fibers not only into the injury but also beyond and into the spinal cord. Extension of axons beyond the site of injury was limited in Bunge’s previous studies utilizing Schwann cell grafts alone. They also found that the combination strategy resulted in more myelinated axons crossing the grafts and more axons that were saved from dying.

The Next Steps
The Miami Project is continuing to advance the knowledge needed to develop new treatments for spinal cord injury. Pearse and Bunge have plans to replicate these findings and improve upon them. Along with clinical colleagues at The Miami Project, they will work to translate these and future findings into trials with humans. “The therapies tested in this study could all be done in humans,” Dr. Kleitman adds. “Rolipram has already been tested in clinical trials for other disorders, and Schwann cells can be grown from patients’ own Peripheral nerves.”

Because rolipram is currently approved for use in humans, one of the initial steps to consider is administration of the drug within a short time after injury. Though not as effective as the triple combination, rolipram alone made a significant improvement. The research team will also be repeating the study to confirm the results and be sure there are no unwanted effects such as the development of pain. Additional studies will be needed to determine if the strategy will be useful in injuries of longstanding duration.

The Miami Project to Cure Paralysis is well positioned to accelerate successful strategies to clinical trial because of the wide-ranging expertise available in this large research center. “This work represents a very important piece of the puzzle for The Miami Project and our efforts to find the cure for paralysis. We feel these results represent real hope for moving our science closer to the clinic and helping those who suffer from spinal cord injury in the near future,” said Miami Project Scientific Director W. Dalton Dietrich, Ph.D.

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