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Rats with Spinal Cord Injury Regain Bladder Function and Some Mobility Following Injection with Novel Drug

ARTICLE IN BRIEF

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CIENTISTS developed an intracellular sigma peptide that allows axons to cross impenetrable barriers, leading to the treatment of spinal cord injuries.

Researchers reported that in rats with spinal cord injury, systemic delivery of a novel drug facilitated functional recovery of locomotor and urinary systems.

More than 80 percent of paralyzed laboratory rats given subcutaneous injections of a novel drug regained bladder function, some movement, or both, according to a study that has generated excitement among spinal cord injury researchers.

Investigators at Case Western University in Cleveland reported that the new drug appears to work by releasing nerve fibers that have become trapped due to scarring from a spinal cord injury, thereby enabling axons to sprout and new connections to form.

STUDY METHODOLOGY, RESULTS

In a series of experiments, a team of researchers led by Jerry Silver, PhD, a professor of neuroscience at Case Western, first tested the novel drug compound called intracellular sigma peptide (ISP) in a laboratory culture, then in 26 rats with spinal cord injury.

“Twenty-one of 26 animals recovered at least one of three behaviors” — the ability to urinate, move, or walk in a grid, which requires a sense of touch and balance, Dr. Silver told Neurology Today. “I've never seen anything like it. There was so much behavioral recovery.”

The results need to be confirmed with further testing in animals before human testing can begin. But experts in spinal cord injury said the findings, reported in the Dec. 3 online edition of Nature, provided an excellent proof-of-concept.

The study builds on 30 years of research by Dr. Silver, who said he has long been pondering the question of why nerve fibers don't grow in certain areas. The paper in Nature helps provide an answer to that question, he said. When a spinal cord injury occurs, a sugar-covered protein called proteoglycan accumulates in scar tissue. Proteoglycans bind with a neuronal receptor to create a sticky, impenetrable net around severed nerve fibers, acting as a barrier to new nerve growth and connections across the scar.

ISP targets the neuronal receptor for proteoglycan, protein tyrosine phosphatase sigma, turning its on/off switch to off. The resulting inability of the nerve fibers to interact with the proteoglycans frees the trapped nerve cells.

Bradley Lang, PhD, the paper's senior author and a graduate student in Dr. Silver's lab at the time, led the rat experiment.

“In spinal cord injured animals, the peptide [ISP] allowed nerve cells to grow” at and especially below the level of injury, Dr. Silver said. Daily injections of the drug were given under the skin, starting on day two after the injury. At first it looked like the experiment was a wash, but after about 10 weeks many of the rats began to recover bladder control, movement, or both. When the researchers increased the dose, 100 percent of the rats were able to urinate much more effectively on their own, Dr. Silver said.

“Systematic delivery of this peptide over weeks restored substantial serotonergic innervation in the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems,” the researchers reported.

Dr. Silver described the effects as an “unprecedented sprouting of nerve fibers” that washed the spinal cord with serotonin. However, it is not clear why some animals recovered certain body functions and other didn't, he noted.

The next step is to test the drug in chronically injured rats, Dr. Silver said. His team also hopes to test ISP in a large animal model, probably a pig, as a step toward human testing.

EXPERTS COMMENT

Commenting on the study, Oswald Steward, PhD, director of the Reeve-Irvine Research Center and senior associate dean for research at University of California, Irvine School of Medicine, told Neurology Today, “I think it's an extremely well-done paper. It builds on a solid history of research and takes it in a new direction.”

Dr. Steward cautioned that robust effects seen in rat studies often don't hold up in human trials, but added that the potential therapeutic implications of the current study are significant.

“If you could restore some measure of bladder function for people with spinal cord injury, that would have a huge impact on their quality of life,” he said.

Lyn Jakeman, PhD, a program director at the National Institute of Neurological Disorders and Stroke, which helped fund the study, likewise advised caution in interpreting the results. “We don't want to raise hopes that this is a magic bullet,” she said.

However, Dr. Jakeman added, “It is an intriguing study and the results were unexpected, even to the investigators themselves.” She said it is particularly noteworthy that the drug appears to promote growth and nerve activity below the level of the injury. Another appeal of the approach is that it involves injections under the skin, not into the damaged spinal cord.

Dr. Jakeman said the findings should help “raise the bar for future research” on spinal cord injury.

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DR. JERRY SILVER: “In spinal cord injured animals, the peptide [ISP] allowed nerve cells to grow” at and especially below the level of injury.

Michael Fehlings, MD, PhD, a professor of neurosurgery and co-director of the spinal program at the University of Toronto, said the report from Case Western was an elegant study that combined in vivo and in vitro research.

“The study focuses on a novel approach to try to unlock the plasticity in the regenerative response in the injured spinal cord,” he said. “I think it is an important study, though there are many questions that arise that will require further work. For one, exactly how is the recovery occurring in the animal model? The exact mechanism remains to be defined.

“A spinal cord injury has complex pathophysiology,” Dr. Fehlings added, noting that the “mechanism of injury differs. Some people will have an injury involving a contusion, others a fracture.”

Dr. Fehlings said he and other researchers doubt that any single drug or therapy will prove to be the remedy for spinal cord injury. Rather, it will likely involve a combination of both neuroprotective and neuroregenerative therapies based on a particular case.

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DR. OSWALD STEWARD: “I think its an extremely well-done paper. It builds on a solid history of research and takes it in a new direction...If you could restore some measure of bladder function for people with spinal cord injury, that would have a huge impact on their quality of life.”

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DR. LYN JAKEMAN said it is particularly noteworthy that the novel drug appears to promote growth and nerve activity below the level of the injury. Another appeal of the approach is that it involves injections under the skin, not into the damaged spinal cord. She said the findings should help “raise the bar for future research” on spinal cord injury.

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DR. MICHAEL FEHLINGS: “I think it is an important study, though there are many questions that arise that will require further work. For one, exactly how is the recovery occurring in the animal model? The exact mechanism remains to be defined.”

LINK UP FOR MORE INFORMATION:

•. Lang BT, Cregg JM, DePaul M, et al. Modulation of the proteoglycan receptor PTPs promotes recovery after spinal cord injury. Nature 2014; Epub 2014 Dec. 3.
    •. Neurology Today archive on spinal cord injury: