Despite remarkable advances in doctors’ understanding of the cascade of secondary events that follow injury to the spinal cord, repairing and regenerating the cord remains a dream work in progress, according to Michael G. Fehlings, MD, PhD, Professor of Neurosurgery and Director of the Neuroscience Program at the University of Toronto, on Friday. Dr. Fehlings, seeking to separate “the hype from the hope,” spoke about spinal cord repair and regeneration at the 30th Mayfield Neuroscience Symposium, where he was the Mayfield Lecturer.The timing was appropriate, as warm summer weather tends to usher in an increase in devastating spinal cord injuries from motor vehicle accidents, falls, shallow-water diving mishaps, and gunshot wounds. Dr. Fehlings’s presentation – he has worked closely with the Christopher & Dana Reeve Foundation – was a reminder that spinal cord injuries are still “forever.”
Dr. Fehlings said that when he sees a 39-year-old man who has suffered a complete spinal injury at C 4-5 after diving into shallow water, “There is nothing I’m able to do that will turn this around and make him like he was before. But part of what we do is try to instill hope in people and get the best we can out of a bad situation.”
Spinal cord injury occurs when the spinal cord, a bundle of nerves that runs down the back from the base of the brain to the waist, is damaged or severed by trauma. If the spinal cord is damaged and is unable to transmit nerve impulses to and from the brain, paralysis occurs.
Following a spinal cord injury, two profound biological events occur: 1) damaged neurons are unable to regenerate their severed axons, the long fibers of communication between the brain and spinal cord that carry sensation and movement signals; and 2) there is an abnormal activation of the protein Rho, resulting in cell death.
Unlike an organ like the liver, which regenerates its tissue, the central nervous system’s ability to repair itself is limited. “It’s stylish to talk about neural plasticity, but there isn’t a lot of it,” Dr. Fehlings said. “The wiring of the central nervous system is complex, and one of the costs of having complex, accurate wiring is the prevention of new, stray wiring. It’s the burden we bear as neurosurgeons: we deal with tissue that’s not very forgiving.”
Scientists have long dreamed of finding a way to disrupt the cataclysmic process of cell death that follows spinal cord injury and results in a life of dependency and permanent disability. For decades typical treatment has involved stabilizing the spine following an acute spinal cord injury, but surgeons had no technologies or medications with which to halt subsequent damage. Today, researchers are marching ahead on multiple fronts.
The recent Surgical Trial in Acute SCI Study showed that prompt surgical intervention, within 24 hours of the injury, is safe and feasible and can improve outcomes, Dr. Fehlings said. Of the 325 patients enrolled, those who had early surgery had better abbreviated injury scale (AIS) scores at six months than those who had late surgery. Steroids also had an effect, and patients who had early surgery and steroids overall had better outcomes. “Further work is continuing to validate these initial promising results,” Dr. Fehlings said.
On another front, a first-in-human, multisite study of a recombinant protein known as Cethrin®, a Rho inhibitor, was shown to limit the devastating process of cell death that occurs following spinal cord injury and to elicit repair of damaged neurons. Charles Kuntz, IV, MD, a Mayfield Clinic neurosurgeon, was principal investigator in the Cincinnati portion of the clinical trial, which sought to determine the safety and the most effective dose of Cethrin® when administered during surgery following acute injury to the spinal cord in the neck (cervical spine) or upper back (thoracic spine). An investigational drug, Cethrin® had not been approved by the United States Food and Drug Administration.
Forty-eight patients were enrolled in the Phase I/IIa trial, receiving Cethrin® an average of just over 48 hours after their injury. Two patients died in the study, and 450 adverse events occurred, none of them related to Cethrin®. “It just shows how sick these patients are,” Dr. Fehlings said. Nevertheless, the trial was considered a success, and a Phase II/b study of the drug is in motion.
Also in the area of neuroprotection, the North American Clinical Trials Network (NACTN) has emerged as a consortium dedicated to furthering the need for improved neuroprotective agents. Supported by the Christopher Reeve Foundation and primarily funded by the Department of Defense, the consortium’s goal is to translate discoveries into treatment.
Currently being investigated is Riluzole, a sodium channel blocker and approved drug currently used to treat patients with ALS. “Sodium is like the thermostat of a cell,” Dr. Fehlings said. “When the cell is injured, sodium enters. That’s why tissues swell. The cell tries to pump it out, which makes it worse, because calcium then goes into the cell. It results in what biologists call a positive feedback loop. So the rationale at looking at sodium channel blockers is clear.” A major multi-center, randomized, controlled trial is expected to begin in early 2013.
That trial will not have industry support, Dr. Fehlings noted. “Industry is not interested in spinal cord injury. Riluzole is a $10-a-day drug, so there is not a lot of profit to be made. But because the lifetime cost of a spinal cord injury runs in the millions, the potential benefits to society are huge.”
Scientists are also studying neural cell-based therapies, in the hope that the spinal cord could be used as a scaffold for restoring remyelinated axons. Scientists are investigating how to reprogram endogenous adult stem cells, which exist within each person’s body, to become neural cells. Introducing these cells into the spinal cord “may be where the future is,” Dr. Fehlings said.
The economics of spinal cord research became evident in this cell-based arena, too, last November, when for business reasons Geron abruptly ended the first clinical trial involving the injection of neural cells derived from embryonic stem cells into the region surrounding a recent spinal cord injury. “That was a bummer,” Dr. Fehlings said, “but the stem cell era in spinal cord injury has begun.”
Finally, scientists must also address the problem of the “glial scar,” the scarred area where the spinal cord injury occurred, and the hole in the spinal cord. “If you introduce stem cells into a compromised environment, you get a zero,” Dr. Fehlings said. Scientists, he said, are studying an enzyme’s potential to dissolve the glial scar as well as a bio-engineering strategy in which self-assembling peptides are injected into the tissue.
“In the next 10 to 20 years, there may be another subspecialty in neurosurgery in which surgeons use techniques to repair and regenerate spinal cord,” Dr. Fehlings said.
More than hype, that spells hope.
–Cindy Starr
