Plugging Up the Injured Spinal Cord

After spending the early 1970s studying regeneration in the Xenopus frog tadpole's optic nerve, Paul J. Reier began to ponder how mammalian spinal cord injuries (SCIs) might heal. Eventually, the junior professor at the University of Maryland School of Medicine chose to enter an emerging field: fetal cell transplantation into the spinal cord. A colleague called the career move crazy--a judgment that Reier now admits wasn't totally unwarranted. "The spinal cord injury field was clouded by pessimism," he explains. "Everything you saw clinically didn't look very promising, and experimentally there were no indications of anything very spectacular on the horizon." Fast-forward two decades: Reier, now a neuroscience professor at the University of Florida College of Medicine in Gainesville, is helping oversee a pioneering clinical trial in which eight SCI patients have received transplants of spinal cord tissue from human fetuses. Papers about the trial have just been published.1,2 In another trial, five SCI patients have received cord tissue from pig fetuses. In animal studies, many labs are treating SCI models with various cell types, ranging from workaday fibroblasts to sexy stem cells. Researchers regularly report that crippled animals regain some degree of function. Alan Tessler, a neurobiology and anatomy professor at Philadelphia's MCP Hahnemann Univer-sity, says he senses "tremendous optimism" in the field. What has happened in 20 years? At least two landmark studies helped dispel researchers' pessimism. In 1980, researchers learned that mammalian central nervous system neurons, long considered inert, could grow if placed beside axon bundles grafted from the peripheral nervous system.3 In 1996, a report appeared that rats treated with such grafts could move previously paralyzed limbs.4 No one, however, foresees immediate prospects of restoring full movement and sensation to lab animals, much less humans, with SCI: the hurdles are too formidable. "No one has yet been able to prove any mechanism for functional recovery in any animal model," asserts John W. McDonald, an assistant neurology professor at Washington University School of Medicine in St. Louis. The spine's complex anatomy renders cause-and-effect relationships particularly elusive. "One must very rigorously prove that a supposedly regenerated axon was really damaged in the first place," notes Larry I. Benowitz, associate neuroscience professor at Harvard Medical School. "In other words, there could be spared axons because the surgery was incomplete." Time-consuming and labor-intensive, SCI studies yield findings that often elicit intense skepticism. Vast Problem, Few Clinical Trials Researchers nevertheless slog on, which is fortunate because the need is so great. About 200,000 Americans suffer from SCI, with 11,000 new cases occurring yearly, according to the University of Alabama at Birmingham's National Spinal Cord Injury Statistical Center. SCIs fall into two broad categories: contusion, typically caused by accidents, and transection, the outcome of bullet and shrapnel wounds. A contused spinal cord gets pinched like a tube of toothpaste as vertebrae slide helter-skelter. Transection involves a partially or totally severed cord. One misconception is that the spinal cord below an injury dies. Many neurons actually survive, causing spasms and pain. They simply cease communicating with the brain and upper spinal cord. © 2000 Society for Neuroscience The dorsal surface of a perfused EG-transplanted spinal cord 6 weeks after surgery. (Journal of Neuroscience 18:3803-15, 1998). Anatomical considerations dictate different treatments for the resulting sensory and motor deficits. Sensory axons emanate from dorsal root ganglia (clusters of neuron cell bodies), which lie next to the spinal cord. Many of these axons extend up to the brain. Restoring sensory function in humans could require that these axons regrow several feet--now a quixotic goal. Motor pathways from the brain to the spinal cord, in contrast, often involve relay cells known as interneurons. Treatments could involve rerouting pathways to nearby non-injured interneurons or inserting cells that could develop into new interneurons. The two current SCI clinical trials in the United States have far less ambitious aims. Seven of the eight subjects in the University of Florida study, begun in 1997, suffer from injury-related syringomyelia, a condition marked by expanding spinal cord cysts that can cause intractable pain and a loss of remaining function. The project is designed to test transplantation safety. The first two patients' physical conditions didn't deteriorate in the 18 months after neurosurgeon Richard G. Fessler drained their cysts and filled them with fetal tissue.1,2 Still unknown is whether transplants will stabilize the cysts and improve function in the long term. Another unknown: whether the grafts have even survived. The team has discovered that magnetic resonance imaging isn't sensitive enough to settle that issue.1 Another clinical trial is being conducted at Albany Medical Center in upstate New York and at Washington University Medical Center in St. Louis. Last April, researchers began injecting five paraplegics and quadriplegics with 14 million to 20 million spinal cord cells from pig fetuses. Diacrin Inc. of Charlestown, Mass., supplies the cells. "We chose the pig because of the similarity to human cells in animal model studies and also the pig's favorable profile in terms of potential infectious agents that could harm the recipient," explains Jon H. Dinsmore, senior director of cell transplantation. The company won't comment about the trial, but McDonald, who is a participating neurologist, says that the procedure appears safe so far. Information about clinical SCI trials in other countries, such as Russia and Mexico, is available at www.sciwire.com. Web site administrator Wise Young acknowledges that many of these studies are poorly documented, and a few could be fraudulent. But he publicizes their existence if only to warn the 600 to 1,000 daily visitors to the site against them. "Many people will go to these trials no matter what we do because there's quite a bit of desperation in this field," notes Young, who also directs the Center for Collaborative Neuroscience at Rutgers University in Piscataway, NJ. "On the other hand, I think it would be doing a disservice to the community, and in general, if we simply hide the trials." Which Cells to Transplant? While mainstream SCI clinical trials focus on safety, animal studies have been far more venturesome. Researchers have transplanted a variety of cell types, hoping that some will blossom into functioning neurons and glia, and that others will provide a milieu upon which native cells can regenerate. Fetal cell transplants have been shown to allow injured rats to develop reflex responses and skilled forelimb activity.5 John D. Houle, an anatomy professor at the University of Arkansas for Medical Sciences in Little Rock, combines fetal transplants with a regimen of muscle manipulation. He and his colleagues move the animals' paralyzed limbs, restoring the hind-limb muscle mass that will be needed for voluntary movement if nerve control is ever re-established. The number of studies applying fetal grafts, however, seems to have dwindled lately. Some scientists want to avoid controversies over fetal tissue use. Another drawback: a single graft typically contains cells from several fetuses, any of which might be immunologically incompatible with the recipient. The current darlings of the SCI field are olfactory ensheathing glia (OEGs).6 OEGs are glial cells that promote axonal growth in the olfactory bulb throughout an animal's life. A paper published last year reported that OEGs enabled rats with complete spinal cord transections to recover locomotor functions and sensorimotor reflexes.7 Alexion Pharmaceuticals Inc., of Cheshire, Conn., is considering a clinical trial in which pig OEGs would be transplanted into humans, according to William L. Fodor, the senior director of xenotransplantation. At the University of Miami School of Medicine, Mary Bartlett Bunge, a cell biology and anatomy professor, has long transplanted Schwann cells into SCI animal models. Easily obtained, these cells normally myelinate axons in the peripheral nervous system. As grafts, Schwann cells can bridge the two halves of a transected spinal cord. But while nerve fibers from the cord grow into the bridge, they don't exit it--a serious drawback--unless OEGs are also injected into the cord's stumps next to the bridge.8 Contusion injuries seem to react differently. Bunge and colleagues at the Miami Project to Cure Paralysis just found that Schwann cell grafts improve axonal regeneration and hind-limb performance better than do OEG grafts. "It's possible that the ensheathing glia did not function normally in the lesion cavity because it's a hostile environment where, for example, excitatory amino acids and free radicals increase soon after injury," she says. Fibroblasts, isolated from the skin, promote limited functional recovery when grafts are engineered to produce neuron-pampering proteins such as neutrophin-3 and brain-derived neurotrophic factor. Though nociceptive (pain-mediating) axons also respond to these factors, this approach does not appear to intensify pain in rats with transected spines, according to recent work by Marion Murray, a neurobiology and anatomy professor at MCP Hahnemann University and coauthor of a book on axonal regeneration.9 She observes that this finding is particularly promising because many patients with severe spinal injuries "report that they would prefer a treatment that diminished pain to one that allowed them to get up and walk." Stem cells are the latest arrows added to the transplant quiver. Washington University's McDonald committed embryonic stem cells (ESCs) to a neural lineage by growing them in retinoic acid-containing medium. He then grafted them into rats' injured spinal cords, and the animals' movement improved.10 He hypothesizes that the ESCs differentiated into oligodendrocytes that myelinated spinal cord axons far more effectively than native, older oligodendrocytes can. These axons, in turn, conducted nerve signals better. Should ESCs be nudged into differentiating into neurons? The fear is that new neurons might inhibit axonal regeneration or make the wrong connections. Evan Y. Snyder, assistant neurology professor at Harvard Medical School who has isolated and transplanted neural stem cells, speculates that the key might be physical training, a neglected area of SCI basic research. Citing evidence that neuronal activity helps guide cell growth, Snyder says, "Physical therapy and non-glitzy interventions like that may allow the appropriate connections to be made." Douglas Steinberg (dougste@attglobal.net) is a freelance writer in New York. References 1. E.D. Wirth III et al., "Feasibility and safety of neural tissue transplantation in patients with syringomyelia," Journal of Neurotrauma, 18:911-29, September 2001. 2. F.J. Thompson et al., "Neurophysiological assessment of the feasibility and safety of neural tissue transplantation in patients with syringomyelia," Journal of Neurotrauma, 18:931-45, September 2001. 3. P.M. Richardson et al., "Axons from CNS neurons regenerate into PNS grafts," Nature, 284:264-5, 1980. 4. H. Cheng et al., "Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function," Science, 273:510-3, 1996. 5. P.S. Diener, B.S. Bregman, "Fetal spinal cord transplants support the development of target reaching and coordinated postural adjustments after neonatal cervical spinal cord injury," Journal of Neuroscience, 18:763-78, 1998. 6. G. Raisman, "Olfactory ensheathing cells--another miracle cure for spinal cord injury?" Nature Reviews Neuroscience, 2:369-74, May 2001. 7. A. Ramón-Cueto et al., "Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia," Neuron, 25:425-35, 2000. 8. A. Ramón-Cueto et al., "Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants," Journal of Neuroscience, 18:3803-15, 1998. 9. N.A. Ingoglia, M. Murray, eds., Axonal Regeneration in the Central Nervous System, Marcel Dekker: New York, 2001. 10. J.W. McDonald et al., "Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord," Nature Medicine, 5:1410-2, 1999.

Plugging Up the Injured Spinal Cord

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