A decade of basic science discoveries in spinal cord repair and regeneration are leading to early-stage clinical trials as researchers agree that they will need to employ a broad range of therapies.
“The state of the art in this field is clearly multidimensional,” said Serge Rossignol, a neuroanatomist at the University of Montreal and a veteran spinal cord researcher. The reason is simple: Spinal cord repair efforts involve multiple steps with different goals: limiting a cascade of secondary damage and stimulating inherent self-repair mechanisms, promoting the regrowth of axons, “rewiring” nerve fibers and ultimately restoring feeling and movement in peripheral nerves and muscles.
Each of these steps represents a high hurdle to overcome; together they present a daunting road to recovery that only a few years ago seemed virtually insurmountable. Yet today, each is the subject of intense investigation that, in a few instances at least, now includes rigorously designed and controlled clinical trials.
“We’re embarking on a remarkable era in spinal cord injury,” said Michael Fehlings, a neurosurgeon and scientist at the University of Toronto, speaking at a symposium in which scientists reviewed the scientific bases for some of the most closely watched clinical trials.
At least nine trials are under way or expected to begin in the next year or so, Fehlings said. The approaches being evaluated include antibodies against a molecule that inhibits nerve growth, infusions of a patient’s own immune cells, and a drug (riluzole) that is currently used to treat amyotrophic lateral sclerosis, or ALS.
A presentation during the symposium by Martin Schwab, a neuroscientist at the University of Zurich, drew a standing-room-only crowd, perhaps in anticipation that he might show preliminary data from an ongoing trial of a neuroprotective and regenerative therapy. Discoveries in the past 10 years in Schwab’s laboratory, including promising work in rats and monkeys, gave rise to the therapy, an antibody designed to nullify a protein, Nogo, that suppresses nerve fiber regeneration.
The human trial’s first phase, to evaluate safety, is nearing completion in Europe and Canada, and a second phase is planned that will include study sites in the United States. No significant side effects have been seen, Schwab said, but he added that it is too soon to evaluate whether the therapy is effective.
“In a year or so, we should know if we’ve seen recovery in patients,” he said at a press briefing.
Meanwhile, a phase 2 (effectiveness) trial investigating an immunotherapeutic approach to spinal cord regeneration has been suspended, said Michal Schwartz, a neurobiologist at the Weizmann Institute of Science in Rehovat, Israel, as researchers try to reformulate the delivery approach to avoid the need for two invasive surgical procedures. The study has been evaluating transplantation of a subset of a patient’s own immune cells, called macrophages, in an attempt to recruit the body’s own self-repair mechanisms. The company founded by Schwartz to develop the therapy, Procord, is pursuing new avenues to get the cells into the spinal cord, including injection directly into the spinal fluid.
Other research groups are pursuing stem-cell based approaches to nerve regeneration. “We’ll see some type of stem cell strategy [entering clinical trials] within a couple of years,” Fehlings predicted.
Vassilis Koliatsos and colleagues at Johns Hopkins University, who are on the front lines of this research, are working in an animal model of ALS. Their research suggests that transplanted neural precursors derived from the human embryonic spinal cord induce significant recovery of motor neurons and that the grafted cells both migrate to the site of an injury and “have all the features of synapses,” Koliatsos said.
These results contradict doubts that stem cells can help with spinal cord repair. “Working with stem cells in the spinal cord was taboo,” Koliatsos said. “The taboo is wrong. There are ways the make the cells you want in the spinal cord.”