SCI Forum Reports
Cell and Gene Therapies: Strategies for Spinal Cord Injury
May 1, 2001
"The neural circuitry in the CNS (central nervous system) is basically a simple system: you need to get information up to the brain, and you need to send information down to the spinal cord," said Howard Nornes, PhD, professor in the Department of Anatomy and Neurobiology at Colorado State University and consultant for the new Spinal Cord Society (SCS) Research Center in Fort Collins, Colorado. Dr. Nornes' talk, "Cell and Gene Therapies: Strategies for SCI," was sponsored by the SCS.
"Each segment of the spinal cord has the same basic neuronal circuitry," he continued. "The primary sensory neurons in the dorsal root ganglia transmit information from the body into the segment; the motor neurons located in the ventral horn of the segment transmit information from the spinal cord to muscles; the ascending projection neurons transmit information from the segment to the brain; finally, the descending projection neurons located in the brain transmit information from the brain to each particular spinal segment."
The nerve cells involved in processing information are called neurons. Each neuron has a nerve cell body, dendrites that receive inputs (information), and a long fiber called an axon that carries signals from the cell body. When a segment of the spinal cord is injured, some of the axons passing through that segment are damaged. But even if the axon is damaged, the cell body may survive. "I think this is an important issue," Nornes said. "It turns out that in experimental animals, the cell bodies of long tract neurons to the spinal cord survive. This is good news as it is the cell bodies that are required for activating regeneration."
Replacing damaged cells and the connections between cells in the nervous system is the focus of much nerve regeneration research today. Nornes has approached this problem first by trying to understand what happens when cells are transplanted into the adult nervous system.
In one experiment, Nornes' team made a cavity in a rat spinal cord, implanted embryonic neurons into the cavity, and found they survived and grew fibers into the host. Next he wanted to know-Can these implanted neurons do anything meaningful? Can they actually restore a function?
Nornes addressed these questions in an experiment using the hind limb reflex system of the rat. In this system, stimulating a specific area in the brainstem will cause the hind leg to flex, which can be measured with a force transducer attached to the foot. If the area in the brainstem is damaged, the reflex function is lost. In his rat experiments, Nornes removed the cells responsible for this reflex, replaced them with embryonic cells, and found that the reflex came back. "This is a demonstration which shows that when you put a cell in the adult nervous system, it survives, it grows fibers, and in this case it restored a specific function," he said.
Another experiment involved making a bridge across the damaged area of the spinal cord. Nornes lesioned the rat spinal cord, implanted embryonic spinal cord tissue, allowed it to heal, and found that the implant formed tissue continuity with the host tissue. "This shows that implanted cells in the spinal cord grow and fill up the space," Nornes said. However, a slide magnifying the transplant area showed that few fibers grow into the transplant from the host. "This again illustrates that few adult neurons are able to regenerate," he said.
Many researchers have been working on this problem. "People have transplanted peripheral nerve cells and embryonic cells. They've used synthetic matrixes. They've added growth factors and antibodies. And in spite of doing all these kinds of things, there is minimal growth of host axons into the transplants," Nornes said. "This is a fundamental issue that we have to deal with to accomplish meaningful regeneration and recovery of function in the injured spinal cord."
One approach has been to try to understand and replicate the process by which growth occurs in the nervous system during embryonic development. "During the development of the nervous system, growth genes are upregulated and drive the growth of the neurons," Nornes said. Once the nervous system is wired up (all the connections are established), this growth program is shut down.
"Our challenge is to identify the key genes that are involved in activating growth, understand how to regulate them, and then regulate them to activate growth," Nornes said.
"The tools of molecular biology are able to accomplish this. It is possible to isolate a particular gene, characterize how to regulate that gene (turn it off or on), and finally, apply appropriate treatments to modify gene expression."
Nornes gave an example of how his research team accomplished this in an experimental SCI model in rats. He and his research team modified the expression of a gene involved in making neurons receptive to a growth factor.
After applying the gene treatment to cells in experimentally injured adult rat spinal cords, he was able to measure an improvement in locomotion and strength. "It was a slight improvement," said Nornes. Nonetheless, "these experiments show that it is possible to make gene-targeted treatments in spinal cord injuries."
While the results are very exciting and promising, Nornes insists that a great deal more work needs to be done. "The good news is that as we learn more about cells and how they can be made responsive to growth factors, we will be able to isolate and regulate and treat the appropriate neurons and activate growth."
The SCS Research Center is staffed and equipped to investigate the problems of chronic SCI at the cellular and molecular level. "What is different at this point in history is that we have the tools to work with this problem at the molecular level," said Nornes. "I think the progress that will be made in the next five years will be very significant in contrast to the last 30 years. It's an extremely exciting time."