In the first hours after a traumatic spinal cord injury, a process of cellular self-destruction known as “progressive hemorrhagic necrosis” (PHN) usually occurs that greatly worsens the initial injury. Doctors have no drug to prevent this process, but a team of neurosurgeons and neurologists recently reported that by briefly blocking the appearance of a protein that helps to cause PHN, in rats with spinal cord injuries, they dramatically reduced the overall spinal cord damage.
A related anti-PHN drug is in early-stage clinical trials, and the team expects that these anti-PHN methods will also be useful in limiting secondary hemorrhage and related swelling (known as cerebral edema) after strokes and other brain injuries.
“What we’re preventing is the secondary injury related to capillaries bursting, which typically doubles the amount of hemorrhage,” says University of Maryland School of Medicine neurosurgeon Marc Simard, principal investigator for the study, which appeared in the April 21 issue of Science Translational Medicine. This secondary bleeding is toxic to nerve cells, cuts off their oxygen supply, and triggers harmful inflammatory processes; it accounts for most of the secondary damage after a spinal cord injury.
“This is a glimmer of light in a relatively bleak field,” says Kristopher Kahle, a neurosurgeon at Massachussetts General Hospital and Harvard Medical School who has done research in this area.
Simard and his colleagues first reported in 2007 that PHN seems to require the presence of a protein known as SUR1 (sulfonylurea receptor 1). In experiments with rodents, they found that damage to the axons (output stalks) of spinal neurons triggers a surge in local levels of SUR1. The protein forms part of a special type of calcium ion channel in the outer membranes of blood-vessel-lining cells known as endothelial cells. After a moderate injury, the sudden abundance of SUR1-associated calcium ion channels may help to protect cells from chemical changes in the surrounding fluid. But after a severe injury, so many of these channels appear that the endothelial cells—and the capillaries they make up—tend to swell until they burst.
In the current study, Simard and his colleagues examined recently-injured spinal cords of humans, mice, and rats and found evidence that in all three, a surge in SUR1 and in the expression of its gene, Abcc8, was associated with the appearance of PHN.
After a spinal cord injury, mice that had been genetically engineered so that their Abcc8 genes were silenced had much less evidence of PHN and associated cell death than control mice who could express Abcc8 normally. They also regained much more muscle control, indicating that the damage to their spinal cords had been greatly reduced.
To prove the role of Abcc8 and its protein SUR1, Simard and his colleagues experimentally injured the spinal cords of rats, which are more similar to humans (compared with mice) in their response to such injuries. Fifteen minutes after the injury, the researchers began to block the translation of Abcc8 into SUR1, using a 24-hour intravenous infusion of a synthetic Abcc8-matching molecule known as an antisense oligodeoxynucleotide. In these animals, the eventual area of spinal damage was reduced to less than one-third of that seen in control animals that had not received the treatment. And again the treated animals fared much better on behavioral tests.
“This really demonstrates that the secondary hemorrhage in these animals was an effect specifically of SUR1,” says Kahle.
Simard and his colleagues obtained similar results by using glibenclamide, a diabetes drug developed in the 1960s. Glibenclamide closes SUR1-associated channels in certain cells of the pancreas, promoting the release of insulin. But it also appears to close the endothelial-cell SUR1-associated channels that activate after spinal cord and brain injuries. In a paper in Nature Medicine in 2006, Simard and his colleagues reported that even low-dose glibenclamide could reduce brain swelling after experimentally induced strokes in rodents.
Because it has been used only as a diabetes drug, glibenclamide is available only in pill form, which could not be taken by unconscious victims of spinal cord or brain injuries. Initial clinical trials are thus testing an intravenously delivered form of the drug. “In terms of the FDA approval process, we’re much further along with glibenclamide,” says Simard. “There’s a Phase 1 trial that is either at the tail end now or is finished, another Phase 1 trial of a different sort that should start in July, and a Phase 2 trial [in spinal cord injury patients] that should start later this year.”
The clinical trials are sponsored by a biotechnology company, Remedy Pharmaceuticals, to which the University of Maryland has licensed the rights to these anti-SUR1 methods. (Simard is an adviser to Remedy, although the company did not sponsor his group’s animal studies.) Simard and his colleagues also have applied to the National Institutes of Health for a grant to perform a clinical trial of intravenous glibenclamide in stroke patients.
Allan Levi, chief of neurosurgery at the University of Miami Hospital, calls the Science Translational Medicine report an excellent paper. Based on the profound effect of the antisense drug or glibenclamide in preventing secondary hemorrhage and limiting nerve function loss, he says, it does appear that such strategies “may have a positive impact in this devastating disease as well as other areas of central nervous system injury.”
The Abcc8-blocking antisense oligodeoxynucleotide strategy hasn’t yet been tested in humans, but Simard thinks it might also be useful someday, perhaps in conjunction with glibenclamide. Antisense drugs have been developed for possible use against several diseases. And although clinical trials have shown that the long-term delivery of these DNA-like compounds tends to evoke unwanted inflammatory reactions, Simard believes that a 24-hour infusion, as in the animal trial, would be unlikely to provoke such a reaction. “I think that the antisense strategy in this case is very promising,” he says.