In his laboratory in Cleveland Clinic’s Lerner Research Institute, neuroscientist Yu-Shang Lee, PhD, painstakingly dissects muscle and dura around the spinal cord of a rat to access the site where the cord was partially severed two months earlier.
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With the help of an operating microscope, Dr. Lee locates the cavity that resulted when the rat’s body responded to the cord injury by forming a cyst. He carefully clears away the scar tissue that surrounds the cavity and prevents axonal regrowth. He then grafts several segments of peripheral nerve into the cavity, injects acidic fibroblast growth factor (aFGF) and an enzyme known as chondroitinase ABC around the site, and sutures the muscle and dura.
For the next six months, Dr. Lee will monitor the animal’s bladder function and locomotion. “Finding a way to improve bladder control in patients with spinal cord injury (SCI) is my near-future goal,” he says.
Dr. Lee has devoted his career to finding potential treatments for SCI and the deficits in motor, sensory or autonomic function it causes. His laboratory concentrates on using nerve-bridging techniques to coax axonal regrowth.
“Pathological changes at the site of SCI create a nonpermissive environment for axonal regeneration. The key to regaining functional recovery is to encourage more axons to cross the damaged site and connect with target neurons,” he explains.
Hope for Improved Quality of Life
Nearly 1.3 million patients in the United States are living with SCI. While regaining motor control remains an overarching goal, patients also desire nearer-term advances that would improve their quality of life. Restoration of bladder control is high on the list.
For four years, Dr. Lee used a National Institutes of Health grant to study bladder restoration techniques in acute SCI. Working with rats whose spinal cords had been completely severed, Dr. Lee and his research collaborator, Jerry Silver, PhD, a Case Western Reserve University neuroscientist, developed a method that enabled severed nerve fibers to grow and reconnect. It involved implanting multiple peripheral nerve bridges for the axons to grow across. The site is injected with growth factor to stimulate nerve fiber growth, and enzymes to digest and eliminate scar tissue around the lesion. Dr. Lee calls this procedure the “full monty.”
Now, his challenge is to determine whether the full monty will produce the same axonal growth and reconnection in animals with chronic SCI. He is seeking additional NIH funding for this phase of the project.
“There is no effective treatment for chronic SCI, which is the current status of most patients with SCI,” Dr. Lee says. “These patients are still waiting. I’m excited about this project, because we have limited knowledge of biology and translational treatment for chronic SCI.”
Figure. Sagittal confocal reconstruction shows how PNG+aFGF+ChABC promotes robust regeneration of chronically injured tyrosine hydroxylase (TH)-positive fibers into the PNG, with many fibers regenerating beyond the PNG/cord interface (A, B). Higher magnification shows spared fibers in ventral portion (C, lower part with arrowhead), and regenerated TH fibers in PNG (C, upper part) and entering caudal cord, where they arborize (C, upper part with arrow). Dashed lines show PNG/cord interface. Scale: A and B, 450 μm; C, 350 μm.
Progress in Chronic SCI
To study chronic SCI, Dr. Lee is using a clinically relevant model of partial injury, the type commonly resulting from car or sports accidents. “The advantage of a rat model is that pathological changes in rats are similar to those in humans,” he says.
After injuring the spinal cord, Dr. Lee waits two months before starting treatment. At that point, lack of bladder control is apparent and continues to worsen until six months post-injury, when the deterioration plateaus. “We consider two months post-injury to be the chronic stage,” he says.
The rats are divided into three groups. Group one receives the full monty of nerve grafts, growth factor and enzyme. Group two undergoes surgery to reveal the site of injury but receives no enzyme or growth factor. The control group receives no treatment after the SCI injury.
Six months later, the effects of treatment are clear.
In the control group and group two, locomotion remains impaired and bladder control has deteriorated.
The rats in group one, however, are significantly better off: The full monty has a limited effect on improving locomotion, but urinary function assessment reveals that a significant amount of bladder control is preserved.
“At the end of the study, these rats were voiding more frequently and efficiently than those in the control groups,” Dr. Lee says. “When we looked at the same rat before and after repair surgery, we could see that deterioration of bladder function had been prevented. But in the rats that didn’t get the full monty, bladder function continued to decline.
“We are not satisfied with simply maintaining function, so we will work on this,” he adds.
Attempts to Boost Nerve Sprouting
Next, Drs. Lee and Silver plan to add another component to the full monty: a novel molecule called intracellular sigma peptide (ISP).
“In addition to being a more powerful way to block the molecular pathway inhibiting nerve regrowth, the protein also can enhance nerve sprouting. Dr. Silver has demonstrated that ISP has a significant effect on both locomotion and bladder control after acute SCI. We’ll now see if it has the same effect in chronic SCI,” says Dr. Lee.
In an area of medicine in which little progress has been made, Dr. Lee’s findings provide a glimmer of hope. Yet they will not move into human clinical trials anytime soon. Dr. Lee plans to move forward with caution.
“We’ll consider using a large animal model to ensure the technique is both effective and safe before moving to humans,” he says.
Dr. Lee is an assistant staff member in Cleveland Clinic’s Department of Neurosciences.