BioWorld International Correspondent
LONDON - A new avenue of research into spinal cord injury has opened up, with the discovery in an animal model that inhibiting cells from entering programmed cell death can help neurons regenerate.
Researchers in Germany have shown that blocking the molecule that normally binds to a cell-surface receptor called CD95 can significantly improve the recovery of mice with artificially induced damage to the spinal cord.
Ana Martin-Villalba, group leader at the German Cancer Research Center in Heidelberg, told BioWorld International: "This is the first time that anyone has shown any success in treating spinal cord injury by inhibiting apoptosis, so this opens up an entirely new field of investigation. It is possible that this could be an adjuvant therapy, given alongside other treatments, to help the patient with spinal cord injury."
Martin-Villalba and her colleagues report their findings in the March 7, 2004, advance online publication of Nature Medicine in a paper titled "Neutralization of CD95 ligand promotes regeneration and functional recovery after spinal cord injury."
One of her colleagues is Peter Krammer, head of the tumor immunology program at the German Cancer Research Center, who in 1989 discovered the receptor CD95, which also is known as Fas. Since then, research has shown that CD95 plays a crucial role in inducing death in tumor cells. Stimulating it causes tumor cells to enter the pathway leading to apoptosis; animals in which stimulation is blocked develop autoimmunity.
More recently, Krammer, Martin-Villalba and their colleagues examined cell death that takes place in the brain when the CD95 receptor is stimulated. That work developed into a study in which they neutralized the CD95 ligand (CD95L) in an animal model of stroke, and found that reduced the size of the area affected by the stroke, in comparison with control animals, which did not have CD95L blocked. The same study showed that blocking tumor necrosis factor (TNF) from binding to its cell-surface receptor could further reduce the size of the infarct in the brain.
"We then asked ourselves whether it might be the same for spinal cord injury, which is also an acute trauma to the central nervous system," Martin-Villalba said.
To investigate that further, the team used a mouse model of spinal cord injury, which involves partially severing the spinal cord at the level of the Th8 vertebra. The procedure causes the mice to become paraplegic.
The first experiments carried out by the group confirmed that many apoptotic cells were present in the area of the lesion, and that cells in the region were expressing CD95, CD95L and TNF. The researchers then tried blocking the activity of CD95L.
"We saw that neutralization of this receptor could protect the mice, which were able to show active movements four weeks after spinal cord injury. But neutralizing TNF did not protect them," Martin-Villalba said. "We were also able to show that, as well as this functional improvement, we could see histologically that there was regeneration of neuron fibers."
Although the regeneration was not on a grand scale, she added, the injury that the mice have is so major that even a small amount of regeneration could be considered a positive response.
Writing in Nature Medicine, the authors of the paper conclude: "Our data clearly show that neutralization of CD95L, but not of TNF, promotes functional recovery after spinal cord injury. For the long-term studies, the neutralizing antibodies were injected shortly before injury to increase their access to the central nervous system after the lesion. Other protocols will need to be devised for applications in the clinical setting."
Martin-Villalba said the team's aim eventually is to evaluate their finding in a clinical setting. A German company, Apogenix Biotechnology AG, of Heidelberg, already is producing for the team a humanized neutralizer for CD95L, which consists of Fc proteins, rather than complete humanized antibodies.
"In the immediate future," Martin-Villalba added, "we want to gain further insight into the mechanism of how neutralization of CD95L has this effect in spinal cord injury. Does it affect only the death of neurons, or is it acting at another level? We already know that this receptor can both induce the death of neurons and help in growing axons."