Development of New Therapeutic Approaches
Ongoing research using animal models to test possible new therapies is progressing more rapidly than ever before. This type of research takes several forms that can best be explained as they apply to solving certain types of damage that result from SCI. There are three major classes of damage to neural tissues that have been identified, each requiring a different therapeutic approach:
- Death of nerve cells within the spinal cord. Because nerve cells lose the ability to undergo cell division as they mature into the highly specialized forms that make up our nervous systems, the death of nerve cells due to injury presents a difficult problem. No Functional connections can be established if the nerves no longer exist. Therefore, replacement of nerve cells may be required.
- Disruption of nerve pathways. When the long axons carrying signals up and down the spinal cord are cut or damaged to the point where they break down after an injury, the parents nerve cells and axons often survive up to the point where the injury occurred. In this case, Regeneration of damaged axons is a real possibility to re-establish connections of nerve circuits.
- Demyelination, or the loss of the insulation around axons. Animal studies and recent studies of human specimens have established that in some types of SCI, the nerve cells and axons may not be lost or interrupted, but that the loss of function may be due to a loss of Myelin sheaths. As described above, myelin sheaths provide insulation so that electrochemical signals are carried efficiently down the long, thin axons. This type of damage may be the most amenable to treatment because rewiring of complex circuits may not be needed and remyelination of axons is known to be possible.
Although specific human injuries may involve any or all types of damage just described, therapies developed to combat any one of them might restore important functions. The "cure" for spinal cord injury may take the form of multiple strategies, each in turn restoring functions that make important improvements in the quality of life for a spinal cord injured individual.
The approach to "cure" research then, is to concentrate on techniques that hold the promise of repairing specific types of spinal cord damage. With the explosion of efforts and progress in the fields of Neuroscience and Molecular Biology (sometimes called genetic engineering), the scope of possible new therapies is wider than ever before.
Replacement of Nerve Cells
Mature nerve cells cannot divide to heal a wound as skin cells can. Replacement of nerve cells requires transplantation of new nerve cells into the site of the injury with the hope that they will mature and integrate themselves into the host nervous system. One approach is to transplant healthy CNS cells from the same animal species. Researchers have been unanimous in their agreement that transplantation of adult nerve tissues does not work, while embryonic or fetal transplantation can be quite successful. The embryonic tissues do grow and develop, and scientists hope that they will form circuits that will return important functions to areas below the injury. Research to date has not supported the hope that host axons would use these grafts as "bridges" across the injury site. An important consideration is that if fetal tissue transplants prove successful in animal models, transferring this approach to human beings will involve important ethical considerations regarding donor tissues and other important questions about immune rejection of cells transplanted from one individual to another.
Another approach that may avoid some of those problems is the use of genetic engineering to manufacture "cell lines" that would work as nerve cells after grafting. This approach involves inserting segments of DNA (genes) into fetal nerve cells that allow the cells to divide indefinitely, creating an ongoing supply of donor tissue. The use of purely neuronal cell lines diminishes the chances of immunological rejection of the grafts. Recently, rodent cell lines have been developed that stop dividing after transplantation (so there is no risk of tumor formation), and that mature into very specialized nerve cells. Research has not yet shown that these cells can restore function after spinal cord injury.
Very recently, scientists have learned that some cells of the adult CNS can be stimulated to divide and develop into new nerve cells. This exciting finding has opened up new possibilities for cell line development without a need for fetal tissue donors.
Regeneration of Damaged Axons
Nerve cells in both the central and Peripheral nervous systems are associated with helper cells called neuroglial cells. After injury, the CNS helper cells largely inhibit regeneration, while those of the peripheral nerves, the Schwann Cells, stimulate regeneration, even in humans. Scientists are attempting to isolate these cells from peripheral nerves and transplant them into the spinal cord to induce regeneration by providing an altered, supportive Environment. In this strategy, a SCI individual could act as their own donor, since Schwann cells can be obtained from biopsies of peripheral nerves in adults.
Schwann cells, nerve cells and some other cells make proteins known to nourish nerve cells called "growth factors". By introducing these factors into injury sites alone or in combination with grafts, researchers hope to stimulate additional nerve regeneration and promote the health of nerve cells. This approach has been shown to stimulate CNS regeneration, including growth of axons from nerve cells within the spinal cord and those from the brain that send their long axons down the spinal cord. Significant restoration of function has not yet been achieved.
Another technique is to genetically alter cells so that they produce large amounts of growth factors and to introduce these into the injury site. While nerve fibers have been stimulated to grow by such grafts, this type of research is in its very early stages. Cells making many types of factors will have to be tested and functional recovery carefully demonstrated.
Remyelination of Axons
Schwann cells are also the cells in peripheral nerves that form myelin sheaths. They are not usually found in the brain or spinal cord where another neuroglial cell, the ogliodendrocyte, is responsible for making myelin. Researchers have shown that Schwann cells grafted into the brain can myelinate central axons. When the loss of myelin is an important part of injury, implanting Schwann cells could stimulate remyelination and thereby restore function.
Another approach involves a drug called 4-aminopyridine (4-AP), which may help demyelinated nerves conduct signals. Animal studies show that a very small percent of healthy, myelinated axons can be enough to carry on important functions in the spinal cord, even in the face of damage to surrounding nerve cells. Helping nerve fibers that have lost myelin to conduct impulses should improve function after injuries that extensively damage myelin sheaths but do not disrupt nerve connections. This research is also in its very early phases.
Summary of Basic Science Research
As you can see by the facts detailed above, the problem of CNS response to injury is incredibly complex. No one theory or approach will overcome all of the effects of SCI, and many scientists now believe that the "cure" will not be found in a single approach, but rather in a combination of techniques. Consequently, it is important for all possible research areas to be addressed so our overall knowledge about how the system works may eventually lead to a cure for SCI.
What about the "imminent breakthroughs" you hear about regularly in the press? It must be remembered that there is a vast difference between a "scientific breakthrough" and a "clinical breakthrough". While scientific discoveries occur quite frequently, clinical (treatment) ones do not. Public announcements of scientific progress help to keep the attention and funding focused on finding solutions to the problems caused by SCI but new scientific breakthroughs generally do not lead to immediate treatment applications.
Researh In SCI Treatment
Drug Treatments For New Injuries
NOTE: It is important to realize these drugs are not a cure for chronic (long-term) spinal cord injuries. It is heart-ening to note, however, that treatments finally are available to lessen the severity of some acute injuries.
Research has shown that all damage in SCI does not occur instantaneously. Mechanical disruption of nerves and nerve fibers occurs at the time of injury. Within 30 minutes, hemorrhaging is observed in the damaged area of the spinal cord and this may expand over the next few hours. By several hours, inflammatory cells enter the area of spinal cord injury and their secretions cause chemical changes that can further damage nervous tissue. Cellular content of nerve cells killed by the injury contribute to this harmful chemical environment. This process may go on for days or even weeks.
Hope lies, therefore, in treatments that could prevent these stages of progressive damage. Drugs that protect nerve cells following injury are now available to lessen the severity of some injuries. Other drugs and combinations of drugs are currently being tested in both animal and clinical trials.
Methylprednisolone
Few treatment approaches have raised as much hope as the announcement by the National Institute of Health that the steroid, methylprednisolone, reduces the degree of paralysis if administered shortly after spinal cord injury.
In clinical trials, an extremely high dosage of methylprednisolone was used in a double-blind study (neither patients nor doctors knew who was getting the exper-i-mental drug). The improvement in some patients was so remark-able that the National Institutes of Health felt it was important to "break the code" (i.e., determine who was getting the drug and who was not) so more patients could potentially be helped.
Overall, the trial showed that while the methylprednisolone treated group retained significantly more function than the placebo group, subjects in both groups experienced chronic loss of function due to their injuries.
Methylprednisolone is effective only if used in high doses within eight hours of acute injury. It is hypothesized that this drug reduces damage caused by the inflammation of the injured spinal cord and the bursting open of the damaged cells. The contents of the damaged cells are believed to adversely affect adjacent cells. High doses of methylprednisolone can lead to side effects, such as suppression of the immune system, but no serious problems have been reported when it is used over a short term as in this study.
Because the success of the methylprednisolone trial had changed the "standard of care" in the United States, subsequent drug trials are now testing the effectiveness of other drugs in combination with methylprednisolone administration. Thus, to demonstrate significant effectiveness, new treatments will have to surpass the functional sparing effects seen with methylprednisolone alone.
Simultaneously, researchers are cooperating to conduct a large multi-center animal study to test the effect of other drugs with or without methylprednisolone.
Tirilizade
Similar positive results to those of methylprednisolone have been achieved in animal studies using another steroid, tirilizade mesylate (Freedox®). This drug, which acts like methylprednisolone, also appears to be effective only if administered within a few hours after injury. From initial animal studies, it appears that this drug may cause less side effects than methylprednisolone. Clinical trials are ongoing.
A large clinical trial with humans is currently underway comparing 48 hour treatment of methylprednisolone with or without added tirilizade. Study results are anticipated to be available in late 1995.
