Five Steps to a Cure
Introduction
I remain impressed by an unprecedented sense of optimism in the scientific community that it will be possible some day to restore function following spinal cord injury. The old dogma that the central nervous system cannot regenerate has now been proven false, and many investigators throughout the world are demonstrating novel ways in which to convert spinal cord tissues nonpermissive for regeneration into permissive ones. Indeed, an exciting fact is that there are multiple ways in which successful regeneration can be induced in the adult central nervous system, which makes it more likely that one day this goal will be achieved in the chronically spinal cord injured individual. Nevertheless, it is more and more clear to me that one simple discovery is not going to directly lead to a cure for paralysis. The concept that one study will uncover the "silver bullet" that will lead to successful regeneration and a cure for paralysis is not likely to materialize. On the contrary, a number of small steps, each bringing us closer to a cure, are most likely the means by which our goals will be met. This is exactly why The Miami Project to Cure Paralysis is such a special and important program. Here, a broad spectrum of researchers, clinicians, and therapists have been brought together to attack the problem of spinal cord injury. Expertise in the fields of electrophysiology, transplantation, surgical interventions, regeneration, and molecular biology are all needed to successfully position the many parts of the puzzle together for successful therapy.
Since its initiation, the Miami Project's goal has been to advance our basic understanding of spinal cord injury and the processes needed to promote regeneration. By bringing together researchers studying both human injuries and animal models, we are striving to accelerate the translation of laboratory successes into clinical applications. Our method to achieve this is to simultaneously develop techniques to better evaluate the natural course of tissue damage and recovery after human injuries, to study similar injuries and innovative therapeutic strategies in clinically relevant animal models, to isolate and grow human cells for transplantation, and then to apply results of animal studies to studies of the human injury. This can only be accomplished by rigorous and objective evaluation of the functional results of new therapies. Our successes to date include:
- groundbreaking pathology studies of the human spinal cord after injury,
- development of new intraoperative monitoring techniques and neuroprotection strategies,
- incisive physiological studies that have described spinal circuits that coordinate human walking and identified new reflexes developing after injury that confirm that the adult human spinal cord can be functionally rewired,
- successful development of methods to isolate and grow large populations of adult-human Schwann cells (growth supporting cells) that promote regeneration of nerve fibers from human central nervous system tissue,
- exciting new work showing various combinations of grafted cells and growth factors promote unprecedented spinal cord regeneration.
Because we are closely approaching a time when a clinical procedure may be available to target paralysis, it is important that we begin to put into place the appropriate stages, or steps, which will be required for a successful therapeutic program to target spinal cord paralysis. With this need in mind, the following concept of five steps to a cure has been advanced.
Step I: Patient selection and pretraining
It is important that discussions be initiated to determine which subpopulations of spinal cord injured individuals may be best targeted for proposed transplantation trials. Spinal cord injury is an extremely heterogeneous neurological disorder, and it is obvious that specific injuries may be more appropriate for certain therapeutic strategies. For example, ongoing discussions relate to whether complete or incomplete spinal cord injured individuals should be first treated. The presence of intact but nonfunctioning white matter tracts may indicate that pharmacological strategies in combination with rehabilitation programs might be most advantageous to promote some degree of functional recovery. In patients with complete lesions, however, strategies that include bridging techniques or cellular transplantation to induce nerve fiber growth across the injured region of the cord will necessitate different surgical interventions. Another point of discussion relates to whether cervical or thoracic lesions should be first targeted for interventions. There is an obvious rationale for targeting cervical lesions, since regeneration over short distances in this region could restore control to many key muscle groups, restoring breathing or arm movements in quadriplegic patients. We must consider, however, that transplantation strategies are invasive and could lead to complications during or after surgeries that could also diminish the health or quality of life of that individual. Thus, surgical strategies targeting thoracic or lower cervical levels may be judged safer; fewer key systems are located near the site of surgical interventions, and critical functions such as breathing would not be endangered. Our researchers regularly participate in this type of discussion at the Miami Project and at symposia around the world; these discussions are ongoing and, we hope, will lead to a clearer understanding and consensus on the pros and cons of each approach.
It is obvious that if we were successful tomorrow in completely regenerating the spinal cord in a chronically injured individual, that individual would not have the necessary cardiovascular or skeletal integrity to stand up and walk away. Thus, it is extremely important that we encourage and better develop specific training programs for chronic patients, to be conducted before surgeries. These will maximize the patients' ability to benefit from restored sensory and/or motor control following the invasive transplantation strategies. It is obvious when visiting the rehabilitation laboratories in the Miami Project's Bantle Center that many chronically injured individuals can benefit from active involvement in various training strategies to improve cardiovascular and muscular tone. Thus, one of our goals is to define specific pretraining strategies targeted for specific surgical interventions, to take advantage of enhanced regeneration in specific spinal cord circuits.
Step II: Surgical interventions and neuroprotection
It is presently not clear exactly how cells or bridges will be effectively implanted in the chronically injured spinal cord patient. Strategies currently being tested to elicit regeneration (Step III, below) involve procedures that are relatively invasive and will demand surgical exposure of segments of the spinal cord and possibly removal of scar tissue. At the very least, intraspinal injection of cells or infusion of growth promoting molecules will likely be required. These may not be restricted to the site of spinal cord damage, but also include relatively intact spinal tissues above and below the structurally damaged site. Methods developed or evaluated in Miami Project laboratories for physiological monitoring of motor nerve function during spine surgeries, and the correlation of MR (magnetic resonance imaging) with anatomical study of damaged cord regions are aimed at helping ensure the safety of surgical manipulations and assisting in the calculation of volumes of cell suspensions that might be needed to fill a cyst or area of spinal cord contusion. It is possible that information gained from recent clinical studies of fetal tissue grafts in spinal cord injured individuals may help us develop a reasonable plan for these surgical interventions.
One active area of investigation within the Miami Project is the development of neuroprotective strategies to protect the spinal cord in the acute injury setting. This work is based on the belief that strategies to limit the degree of primary injury will limit the severity of neurological deficits produced by the trauma and enhance measures to promote recovery of function. Recent data from various laboratories have indicated that neuroprotective strategies currently being used in the acute setting may also have beneficial effects on transplantation strategies to target regeneration. A problem with the cellular transplantation literature has, for many years, been that only a small percentage of implanted embryonic nerve cells or stem cells may survive when injected into the adult nervous system. Possibly, transplantation strategies combined with neuroprotective agents to promote survival and regeneration may be more successful. One area that the Miami Project is specifically targeting has to do with post-traumatic inflammation and the effects on successful regeneration. Thus, the use of anti-inflammatory agents or other neuroprotective strategies prior to or in combination with surgical interventions may well be an important new strategy in the field of spinal cord regeneration.
Step III: Transplantation/regeneration
Currently, two major strategies are being used in laboratories throughout the world to promote regeneration following spinal cord injury: introducing cells or agents into the spinal cord that promote growth or others that overcome barriers to growth (Step IV, below). The first deals with replacing the hostile environment in the site of injury using bridging strategies, specifically using peripheral nerves. This strategy has been discussed since the turn of the 20th Century, but successes in Canadian and British laboratories in the early 1980s helped jump-start a revolution in regeneration research. Data from Sweden in 1996 showed successful regeneration and recovery of function in the rodent model of spinal cord injury, using a complex grafting strategy of multiple peripheral nerves along with the administration of a neurotrophic factor. Unfortunately, the degree of regeneration and recovery of function published in that study has not been confirmed by researchers in other laboratories. Therefore, it is currently unknown whether peripheral nerve bridges represent the best approach to bridging the gap in spinal cord following complete injury.
The Miami Project, as well as other investigators throughout the world, have been using helper cells, a related approach, to promote regeneration. The Miami Project has pioneered the use of Schwann cells to promote regeneration; these are the cells within peripheral nerves that promote nerve growth and remyelination. Methods have already been developed to acquire the cell populations needed for human autotransplantation, and our research has shown that these cells effectively elicit neurite growth from adult human CNS (central nervous system) cells. Transplantation studies have repeatedly demonstrated that transplanted Schwann cells promote regeneration in animal models of spinal cord injury. Although their ability to enhance successful axonal regeneration beyond the extent of the grafts is limited, recent data have suggested that the combination of olfactory ensheathing glial cells together with Schwann cells enhance regeneration far beyond the graft site into host target areas. Neurotrophic factors (growth-promoting factors) also enhance regeneration, and an exciting direction of current research deals with genetically engineered Schwann cells or fibroblasts to synthesize and secrete specific neurotrophins in an attempt to provide more robust regeneration. Studies are ongoing, therefore, to determine what combination of cells and growth factors may best be used to promote successful regeneration and restoration of function. This is an extremely active field of research, and scientists agree that a combination of strategies, including transplantation and growth factor administration will most likely be needed for the cure.
Step IV: Overcoming barriers for regeneration
An important advance in recent years involves the demonstration of inhibitory factors that reduce spontaneous or transplant-induced axonal regeneration following spinal cord injury. Various molecules, originating from myelin as well as inflammatory and glial cells, have been suggested to retard regrowth. Although this retardation of regeneration was originally felt to be due to a structural barrier (glial scar), more recent data indicate that a biochemical barrier produced around the area of spinal cord injury isolates the injured tissue from the healthy tissue and prevents growth across the barrier. Antibodies and enzymes are currently being developed by scientists at universities and biotechnology companies to target the formation of these inhibitory molecules, with the view that robust regeneration may be induced when these molecules are removed from the injury setting. Thus, the addition of growth-promoting agents (Step III, above) in combination with removal of inhibitory factors is felt to be an important approach in our goal of successful regeneration.
Step V: Rehabilitation
It is apparent from a vast amount of experimental and clinical literature that rehabilitation strategies after CNS injury improve motor and sensory function. Clinical trials are currently ongoing within the Miami Project and at other centers to develop novel strategies to improve motor performance in patients with complete and incomplete spinal cord injuries. Some natural rewiring of spinal circuitry after injury has been demonstrated, as has the spinal cord's ability to "learn," i.e., strengthen existing neural patterns, such as reflexes or spinal locomotion rhythm generators, following training. It is clear from the experimental brain literature that the environmental surroundings of an injured animal, including the amount of sensory input, appears to play a major role in patterns of recovery. It is also clear that, even with successful regeneration of the injured spinal cord, a great deal of rehabilitation will be necessary to guide or modify newly growing circuits to perform necessary functions. Indeed, it is hoped that motor rehabilitation training currently being tested in the Miami Project will serve to provide baseline data that will be quite important when assessing the effects of many of our transplantation and pharmacological strategies in the future. We hope that the pretraining procedures summarized in Step I of this five-step plan will be directly coupled to the post-surgical rehabilitation techniques currently being tested in the Bantle Center.
In summary, this five-step program describes individual stages that we feel are each extremely important in achieving our ultimate goal: promoting functional recovery following spinal cord injury. Again, many of the techniques and procedures that have been discussed are being investigated and evaluated simultaneously within the Miami Project to accelerate progress toward a cure. A major advantage of our ongoing programs is that novel information or new discoveries from other laboratories throughout the world can easily be inserted into this five-stage plan so that successful regeneration and a cure will be found in the future. It is felt that many of these investigations will also have an impact on quality of life issues such as pain, spasticity, autonomic functions and male fertility in spinal cord injured persons. Finally, it is important to stress that this five-step plan is an initial attempt to organize our program and will be revised as new information is received. |
|
