Spinal Cord Injury: Harnessing Regeneration and Immune Defenses
Harnessing Regeneration and Immune Defenses


by Brenda Patoine

January, 2004

Wise Young, M.D., Ph.D.

Professor and Founding Director

W.M. Keck Center for Collaborative Neuroscience Chair, Department of Cell Biology and Neuroscience Rutgers, The State University of New Jersey

 Q: How would you characterize the pace of progress in spinal cord injury repair, and what key factors account for that pace?

WY: Spinal cord injury repair research has been moving very rapidly. Some highlights:

  1. Axonal growth inhibitor theory. Since 1991, when Martin Schwab and colleagues first reported that an antibody called IN-1 stimulated spinal axons to regenerate, the field has made enormous progress. The protein that IN-1 blocked and that apparently inhibits axonal growth in the spinal cord was isolated in 2000 and named Nogo. In addition, other proteins have been reported to stop axonal growth in the spinal cord, including myelin-associated pro­teins MAG and OMgp, as well as chondroitin-6­sulfate proteoglycan (CSPG). In 2001, Stephen Strittmatter and colleagues discovered the Nogo receptor.
  2. Cell transplantation therapies. In the meantime, cell transplant therapies for spinal cord injury have progressed rapidly. Many dif­ferent kinds of cells have been transplanted into the injured spinal cord to improve the environ­ment for axonal regeneration at the injury site. Several cell transplants have now been reported to stimulate regeneration and improve function­al recovery after spinal cord injury in rats. The most exciting has been olfactory ensheathing glial (OEG) cells. OEG cells are very special cells that are made in the nasal mucosa and migrate up the olfactory nerve to the olfactory bulb. They stimulate regeneration of olfactory axons and also can remyelinate them, perhaps explaining why the olfactory nerve is the only one in the central nervous system that continu­ously regenerates in adults.
  3. Growth factors. Although nerve growth factors and other neurotrophins were discovered many years ago and several studies have report­ed that they stimulate axonal growth in the spinal cord, the work did not achieve critical mass until recently, when several laboratories reported that combination neurotrophin thera­py, i.e. NGF, BDNF, and NT-3, stimulate axon­al growth better than each of the growth factors individually. Very recently, several groups reported functional improvement and better axonal regeneration in injured spinal cords when glial-derived neurotrophic factor (GDNF) was applied or expressed in the spinal cord.

These findings are also consistent with recent reports that OEG cells express these factors, which may account for some of their beneficial effects.

These therapies represent only some of the “hot” therapies that are being investigated. Many drugs and even physical treatments of the spinal cord may be useful for restoring function in spinal cord injury. There is thus much reason for hope that doctors will soon be able to repair injured spinal cord even many years after injury.

Q: Over the years, a number of animal studies have shown promising results in inducing func­tional recovery after spinal cord injury. What is the biggest challenge (or challenges) to translating these advances into new treatments for patients?

WY: We need more clinical trials of therapies for spinal cord injury. For many years, the phar­maceutical industry regarded spinal cord injury as a small and risky market for which to develop therapies. Combined with the traditional pes­simism that dominated the field, there was vir­tually no industry investment in clinical trials. The National Institutes of Health funded the first and few clinical trials on spinal cord injury therapies. These include the first demonstration of methylprednisolone as a neuroprotective therapy for human spinal cord injury.

At the present, there are several spinal cord injury clinical trials. The first and largest trial involves 4-aminopyridine (Fampridine SR), which increases excitability of demyelinated axons and may reduce spasticity, improve motor strength, and enhance sensory function in people with chronic spinal cord injury. Several smaller trials are examining transplantations of porcine fetal stem cells, human fetal olfactory ensheathing glia, and adult human olfactory ensheathing glia.

There are, in addition, many promising therapies that have been reported to improve recovery in animal spinal cord injury models and can be taken rapidly to clinical trial but have not yet done so. For example, GDNF was reported to protect the spinal cord and stimulate regeneration. Combination neurotrophins have also been reported to stimulate regeneration and improve recovery. Several therapies that block axonal growth inhibitors have not yet reached clinical trial, even though they were discovered over a decade ago.

So, our greatest challenge is encourage more investment into clinical trials by the industry and government. At the present, total invest­ment into spinal cord injury research in the U.S. is probably less than $100 million. The pharmaceutical industry estimates that it costs on average $800 million to move one therapy from discovery to market. Without investments of this magnitude either by the industry or gov­ernment, progress in translating research from bench to bedside will be slow.

Q: Does pressure from patient advocacy groups to develop treatments rapidly help or hinder scientific research in this area? Why or why not?

WY: Pressure from patient advocacy groups to develop treatments rapidly does help. The groups not only provide a much-needed sense of urgency and priority to the field but also have helped increase federal and private funding of research. Christopher Reeve, for example, has probably done more to bring spinal cord injury to public attention than anybody. It is impor­tant, however, that the pressure from patient advocacy groups is based on a realistic and rational understanding of the goals and challenges. Although pressure for more clinical trials is good, we must be careful not to stop or slow down basic research aimed at understand­ing mechanisms of spinal cord injury, regenera­tion, remyelination, and recovery. The pipeline of therapies must continue to flow if future therapies will become better.

Pressure from patient advocacy groups…provides a much-needed sense of urgency and priority to the field.

Q: What are the research areas to watch in the year ahead in spinal cord injury research?

WY:I am very proud of our field and how it has contributed novel therapeutic approaches to central nervous system disorders. These include therapeutic vaccine, stem cells, and gene thera­py. Several groups have reported that vaccina­tion can induce regeneration and recovery in animals with spinal cord injury. This is a remarkable concept. If you had asked me sever­al years ago whether it would be possible to regenerate the spinal cord by vaccination, I would have said no. Likewise, many groups have reported that stem cells can be transplant­ed and improve recovery in animal models of spinal cord. We did not even know about adult stem cells until five years ago.

Finally, gene therapy has come into its own in spinal cord injury. The first spinal cord injury gene therapy studies were carried out by modifying skin cells (fibroblasts) to express neu­rotrophins. Now, not only has use of genetically modified cells become common, scientists are transfecting genes into the spinal cord and showing neuroprotection, regeneration, and remyelination. 

 
Michal Schwartz, Ph.D.

Professor of Neuroimmunology The Weizmann Institute of Science Rehovot, Israel

Q: How would you characterize the pace of progress in spinal cord injury repair, and what key factors account for that pace?  

MS: I have been working on the problem of recovery from central nervous system (CNS) injuries for the last 25 years. In the beginning my work was more general and was aimed at resolving basic aspects related to the question of why CNS axons of mammals do not regenerate after an injury. Looking back on the progress in general, and in my own research in particular, I can say without hesitation that the major changes that have taken place in this field give us reason for optimism, not only at the level of basic science but also in its clinical aspects. Scientists in the field are now more open to new concepts and strategies, and consequently there is less resistance to acceptance of new ideas and greater interest in developing new therapies.

For years before I began my research, the dogma was that activated immune cells found in the CNS are harmful intruders.

 From my own perspective, it is clear that the field has undergone a dramatic change. For years before I began my research, the dogma was that activated immune cells found in the CNS are harmful intruders. This was the assumption underlying all work done on dis­eases or disorders of the brain or spinal cord. Since there was no knowledge of how brain injury might resolve itself without immune cells, there was nothing to counter the negative bias. The entrenched perceptions distorted the interpretation of observed phenomena and impeded progress in the field. 

Q: You first showed in 1998 that injecting macrophages into paraplegic rats stimulated partial recovery of motor function, and this technique is now being pursued in patients with spinal cord injury. What has been the biggest challenge in translating this advance into a viable clinical therapy?  

MS: Discovery of the beneficial effect of autolo­gous macrophages was a turning point in my research. Years before that, there were already indications from some of my experimental results that immune cells play a pivotal role in therapy. I found that much of the existing litera­ture could not be reconciled with my observa­tions. I knew that I was going out on a limb, but I was willing to risk my career by asserting that the immune system might have a positive, not to say essential role in CNS repair, and that by refusing to acknowledge the possibility we were not only failing to understand the physiology of the immune system but also denying victims of CNS injury the chance to benefit from suitable therapy as well as from their own inherent mechanisms of repair. 

Translating this concept into a therapy, however, was not a simple matter. There was an inevitable debate: Should its application to development begin right from the start or should it wait for successive generations while in the meantime the scientists continue to extend basic knowledge and improve tech­niques. I chose to continue with the basic research and help translate it into a treatment modality. For the latter, it was necessary to (a) transfer the experimental animal technologies to an industrial research and development com­pany, (b) optimize the rat model, (c) develop a method for use in humans, (d) extrapolate existing data to a protocol for clinical trials, and (e) ensure that the human protocol was safe. 

Q: Your recent paper in the Journal of Neuroscience showed that a vaccination technique using dendritic cells can also promote functional recovery from spinal cord injury in rats, possibly via a transient induction of autoimmunity. Can you explain why inducing an autoimmune response seems to be a good thing in this case?  

MS: As a follow-up of the work with macrophages I addressed the phenomenon of dialog between the immune system and the CNS in a more general way. This led me to a fundamental observation that has resulted in a paradigm shift, not only in neurotrauma, but in immunology in general and particularly in the perception of neurodegenerative and autoim­mune diseases in the CNS. The finding, simply stated, was that autoimmunity, until that time considered to be a physiological aberration and always detrimental to the organism, is actually a mechanism of self-repair, and causes an autoim­mune disease only when it is malfunctioning. 

This revelation led my group to embark on the search for a safe way to boost this potentially beneficial form of immunity, understand what makes it beneficial, and find out what regulates it. Our studies led us to view inflammation not as a malfunctioning bodily response, but as a response whose function is defense and mainte­nance. It further suggested that an inflammatory response in conjunction with diseases does not necessarily imply that inflammation is part of the pathology. It might instead be part of a repair process, which however is insufficient or inap­propriate for the purpose. If so, by suppressing it we deny and eliminate its potential benefit. 

We formulated the concept of autoimmunity as the body’s mechanism of defense and repair. This led us to realize that injury to the spinal cord or any other part in the CNS leads to an efflux of destructive self-compounds that can rightly be regarded as the enemies within and that fighting off these enemies requires a special anti-self fighting force, such as autoimmunity. 

In investigating the mechanism of this response to self we discovered that the role of autoimmunity is to control the behavior of microglia in such a way that they develop into a phenotype whose function is not, as is usually the case, to kill invading microbes, but to fight off and remove destructive self-compounds. By applying treatments that counteract autoimmu­nity or prevent any immune regeneration, not only do we deny the fighting force of the local immune cells (microglia), but we leave open the possibility of their development into destructive (disease-causing) cells. 

Q: How has this new view of autoimmunity opened the door to novel therapeutic approaches?  

MS: In the absence of any intervention, the potentially neuroprotective microglia are either insufficient or are not activated early enough to exert their beneficial effect. Our new view of autoimmunity and its role in neurodegenerative conditions led us to search both for antigens that would safely boost autoimmunity upon need and for a physiological mechanism that would maintain the balance between the need for autoimmunity and its attendant risk. In seek­ing such an antigen we discovered that the synthetic copolymer 1 (Cop-1; Copaxone), a drug approved by the FDA for treatment of multiple sclerosis, can act as a weak agonist of a range of self-reactive T cells. 

When used by our group (and subsequently by others) as a vaccine in several models of neurodegenerative disorders, Cop-1 showed strong neuroprotective properties by activating microglia in a well-controlled way and by serving as a source of growth factors and neurotrophins. 

As a direct outcome of the knowledge gained of the dialog between T cells and microglia/ macrophages and the role of such dialog in CNS repair, clinical trials in patients with neurodegenerative diseases treated with this T cell-based therapeutic vaccination are now under way. We further discovered that a sub­population of naturally occurring regulatory immune cells (CD4+CD25+), via brain-derived neurotransmitters, serves as a physiological control mechanism that enables the body to manifest autoimmunity without risk of auto­immune disease. 

Taken together, these findings have led us to a broader view of the nature of communication between the immune system and the brain. We are currently investigating their implications for higher brain functions.

Q: Does pressure from patient advocacy groups to develop treatments rapidly help or hinder scientific research in this area? Why or why not?  

MS: The knowledge that victims of spinal cord trauma and other devastating CNS injuries, now and in the future, have a desperate need for an effective therapy has influenced scientist motivation to pursue this field of research, but has not created any undue pressure to rush prematurely into clinical trials. 

Q: What are the research areas to watch in the year ahead?  

MS: The year ahead will see research in which different treatment modalities are combined with immune-based therapy, including stem cells. In addition, growing insight into the brain-immune dialog can be expected to lead scientists to explore the role of the immune system in higher brain functions, opening the way to new avenues of immune-based therapies for neurodegenerative diseases, possibly including dementias and mental disorders.

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Rats with spinal cord injuries showed improved recovery, better preservation of neural tissue, and significantly smaller cysts when treated with dendritic cells that were primed with a myelin peptide to induce “protective autoimmunity.”