Simply implanting progenitor cells into the cord may be enough to prod them to multiply and differentiate into the needed lineages and thus to replace useful numbers of lost neurons and glial cells and establish the proper synaptic connections between neurons. Stem cells transplanted into the normal and injured nervous systems of animals can form neurons and glia appropriate for the region of transplantation. Combined with the fetal tissue results, this outcome signifies that many important cues for differentiation and targeting preexist in the injured nervous system. But if extra help is needed, scientists might be able to deliver it through genetic engineering. As a rule, to be genetically altered easily, cells have to be able to divide. Stem cells, unlike mature neurons, fit that bill.
Scenarios involving stem cell transplants are admittedly futuristic, but one day they themselves may become unnecessary, replaced by gene therapy alone. Delivery of genes into surviving cells in the spinal cord could enable those cells to manufacture and release a steady supply of proteins able to induce stem cell proliferation, to enhance cell differentiation and survival, and to promote axonal regeneration, guidance and remyelination. For now, though, technology for delivering genes to the central nervous system and for ensuring that the genes survive and work properly is still being refined.
Until, and even after, cell transplants and gene therapies become commonplace for coping with spinal cord injury, patients might gain help through a different avenue—drugs that restore signal conduction in axons quieted by demyelination. Ongoing clinical tests are evaluating the ability of a drug called 4-aminopyridine to compensate for demyelination. This agent temporarily blocks potassium ion channels in axonal membranes and, in so doing, allows axons to transmit electrical signals past zones of demyelination. Some patients receiving the drug have demonstrated modest improvement in sensory or motor function.
At first glance, this therapy might seem like a good way to treat multiple sclerosis, which destroys the myelin around axons of neurons in the central nervous system. Patients with this disease are prone to seizures, however, and 4-aminopyridine can exacerbate that tendency.
Neurotrophic factors, such as NT-3, that can stimulate remyelination of axons in animals could be considered for therapy as well. NT-3 is already entering extensive (phase III) trials in humans with spinal cord injury, though not to restore myelin. It will be administered by injection in amounts capable of acting on nerves in the gut and of enhancing bowel function, but the doses will be too low to yield high concentrations in the central nervous system. If the drug proves to be safe in this trial, though, that success could pave the way for human tests of doses large enough to enhance myelination or regeneration.
The Years Ahead
Clearly, the 1990s have seen impressive advances in understanding of spinal cord injury and the controls on neuronal growth. Like axons inching toward their targets, a growing number of investigators are pushing their way through the envelope of discovery and generating a rational game plan for treating such damage. That approach will involve delivery of multiple therapies in an orderly sequence. Some treatments will combat secondary injury, some will encourage axonal regrowth or remyelination, and some will replace lost cells.
When will the new ideas become real treatments? We wish we had an answer. Drugs that work well in animals do not always prove useful in people, and those that show promise in small human trials do not always pan out when examined more extensively. It is nonetheless encouraging that at least two human trials are now under way and that others could start in the next several years.