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Gene-Targeted Therapy Might Help Prevent Paralysis
Date:4/21/2010

In rats, approach minimized dangerous bleeding around spinal cord

WEDNESDAY, April 21 (HealthDay News) -- A study in rats is raising new hope for a treatment that might help spare people with injured spines from the paralysis that often follows such trauma.

Researchers found that by immediately giving injured rats a drug that acts on a specific gene, they could halt the dangerous bleeding that occurs at the site of spinal damage.

That's important, because this bleeding is often a major cause of paralysis linked to spinal cord injury, the researchers say.

In spinal cord injury, fractured or dislocated bone can crush or damage axons, the long branches of nerve cells that transmit messages from the body to the brain. But post-injury bleeding at the site, called progressive hemorrhagic necrosis, can make these injuries worse, explained study author Dr. J. Marc Simard, a professor of neurosurgery, pathology and physiology at University of Maryland School of Medicine in Baltimore.

Researchers have long been searching for ways to deal with this secondary injury.

In the study, Simard and his colleagues gave a drug called antisense oligodeoxynucleotide (ODN) to rodents with spinal cord injuries for 24 hours after the injury occurred. ODN is a specific single strand of DNA that temporarily blocks genes from being activated. In this case, the drug suppresses the Sur1 protein, which is activated by the Abcc8 gene after injury.

After routine injuries, Sur1 is usually a beneficial part of the body's defense mechanism, preventing cell death due to an influx of calcium, the researchers explained. However, in the case of spinal cord injury, this defense mechanism goes awry. As Sur1 attempts to prevent an influx of calcium into cells, it allows sodium in, Simard explained, and too much sodium can cause the cells to swell, blow up and die.

In that sense, "the 'protective' mechanism is a two-edged sword," Simard said. "What is a very good thing under conditions of moderate injury, under severe injury becomes a maladaptive mechanism and allows unchecked sodium to come in, causing the cell to literally explode."

However, the new gene-targeted therapy might put a stop to that. Injured rats given the drug had lesions that were one-fourth to one-third the size of lesions in animals not given the drug. The animals also recovered from their injuries much better.

"The results in rats were quite dramatic," Simard said. "The rats did a whole lot better. In some, it was hard to tell that they were injured at all."

The study, which received funding from the Veterans' Administration, the U.S. National Institutes of Health and the Christopher & Dana Reeve Foundation, is published in the April 21 issue of Science Translational Medicine.

Importantly, researchers also found elevated Sur1 and sodium in human spinal tissue taken from people who had died shortly after suffering a spinal cord injury. That strongly suggests that a similar process occurs in people and could be treated the same way, Simard said.

Antisense oligodeoxynucleotide is currently used in the treatment of some cancers and diabetes, although there are concerns about side effects from its long term use. Challenges also remain in terms of getting the drug to target the right tissue or cells, Simard said.

However, in spinal cord injury, the treatment, which is given intravenously, is short-term and poses few risks of side effects, Simard said. In the injured rats, the ODN went into the bloodstream and targeted the endothelial cells of the capillaries, where the bleeding around the spinal cord was coming from.

After just 24 hours, rats were removed from the IV and the bleeding did not continue, according to Simard.

The researchers are seeking FDA approval to begin Phase 1 or 2 clinical trials using either oligodeoxynucleotide or similar drugs that work on the same pathways.

"It is highly effective, the side effects are nil and this is something that could be given quite early, even in the field or in the ambulance on the way to the hospital if it is proven to be safe, which I believe it is," Simard said.

Dr. Robert Grossman, chairman of neurosurgery and director of the Methodist Neurological Institute in Houston, said the findings were promising.

"A great deal is known about these drugs and they are generally quite safe," Grossman said. "People have been looking for a long time of blunting the secondary injury. There are multiple ways of attacking the same process, but this is a very promising way."

Such treatments may also one day be used to help staunch bleeding in brain injury, Grossman noted.

Every year, about 11,000 people in the United States suffer spinal cord injury, according to background information in the study.

More information

The Christopher & Dana Reeve Foundation has more on spinal chord injury.



SOURCES: J. Marc Simard, M.D., Ph.D, professor, neurosurgery, pathology and physiology, University of Maryland School of Medicine, Baltimore; Robert Grossman, M.D., chairman, neurosurgery, and director, Methodist Neurological Institute, Houston; April 21, 2010, Science Translational Medicine


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