Fifteen years ago, it did not seem likely that there would be treatments for paralysis, but major recent developments have shown that there is good reason to hope. While treatments are still in the future, our understanding of how the body reacts after an injury and what we can do to help repair the damage is growing at a fantastic pace. Moreover, there are many new technologies emerging that allow us to ask questions and look for answers in ways unthought-of only 5 years ago.
To find treatments for spinal cord injury, we need to explore the nervous system, the response of the immune system, how things developed in the first place, what various drugs do, and what the anatomy looks like. Each of these, and this list in incomplete, is a highly specialized field of study. Generally, scientists focus their research on only one of these areas, and that is a full time job. Each is a small part of the SCI puzzle. To put the puzzle together, scientists need to work together and they need to communicate. One goal of the RIRC is to serve as a central hub for research information on SCI, bringing together scientists in California and across the globe. In addition to fostering collaborations and communication among scientists, we realize the necessity of including people with SCI, physicians, and rehabilitations experts in the dialogue. It is only through working together as a group that real treatments will be found and moved into people.
The RIRC, however, is not only a place that brings people with a vested interest in SCI together, it is a major research facility in it own right. We are devoted to studies of basic cellular and molecular mechanisms that underlie the response of the nervous system to injury, and to use that understanding to develop treatments for SCI. The RIRC has 4 primary investigators and 15 Center Associates exploring different aspects of neural repair and SCI. Each is looking at a piece of the SCI puzzle.
Containing Secondary Damage
After the initial trauma to the spinal cord, the body reacts with an immune response that leads to swelling, inflammation, and clean up of dying cells. Unfortunately, this response can also cause tremendous damage. The damage created by the body's response is called secondary damage or secondary degeneration. The result of this is a large hole, or fluid filled cyst, in the spinal cord going millimeters to centimeters above and below the initial trauma site. To someone with SCI, this can mean a tremendous difference in residual ability, for example being able to control your hands or not. If we understand why cells continue to die after the trauma, we can look for ways to prevent cell death and keep the damaged area to a minimum, and an individual's capabilities to a maximum. The RIRC is attacking this part of the SCI puzzle from several angles.
Surprisingly, it is only recently that scientists have really started paying attention to the role of the immune system after SCI. One critical part of the immune system is called the compliment cascade, and until Dr. Aileen Anderson began studying it, no one knew about its role after SCI. The complement cascade is one means by which inflammation can cause cells like neurons and oligodendrocytes (myelin makers) to die. Complement does this through the formation of the 'Big Mac', or membrane attack complex (MAC). Only this MAC doesn't include french fries and a coke. Instead, this MAC makes a hole in the cell, and if enough MACs are formed on the surface of the cell, the cell dies. Usually it is invading cells like bacteria and viruses that are attacked by complement created MAC. However, after SCI, many damaged but surviving cells in the spinal cord are 'tagged' for removal by the complement system even though it is possible that these cells could recover and function again. Dr. Anderson's work suggests that for spinal cord injury, rather than cleaning up dying and damaged cells immediately, a better overall strategy might be to block the inflammatory response early on. Dr. Anderson is working on ways to change the compliment cascade, and so change the amount of damage following injury.
The complement cascade is one component of the immune response after injury. Dr. Hans Keirstead, in collaboration with Dr. Tom Lane, an immunologist studying MS at UCI, is exploring another. They found that immune cells, specifically destructive T-cells, flock to the injury site within hours of injury. Drs. Keirstead and Lane have identified a key molecule that brings the destructive T-cells into the injury. This molecule, IP-10, is like the soldier who plays reveille and calls the troops out. Dr. Keirstead has found that if bugle is not blown, the destructive T-cells do not come into the injury site, and over 70% of the tissue that would have been destroyed is saved.
To take the next step from lab bench to clinical trial, Dr. Keirstead formed Ability Biomedical, a small biotech company, to carry out the preclinical research. Preclinical studies make sure that the treatment is not toxic to human tissue, explores when the treatment should be given and at what dose, dn repeats the studies in multiple species. Last fall this technology was sold to a larger biotech company, Medarex, who has announced it will be talking this treatment to clinical trail in humans in 2005. However, they will likely not being going in SCI first. It turns out, the immune system cell that recruits the destructive T-cells in SCI is also the bad guy in MS, rheumatoid arthritis, inflammatory bowel disease, and certain forms of macular degeneration. There are far more people with, for example, rheumatoid arthritis, 2.1 million in the USA, than there are new SCI injuries, 11,000 in the USA per year. Also people with a disease like rheumatoid arthritis are more stable, not having multiple other injuries that are frequently seen following SCI, making a clinical trial easier in that population.
From our point of view, this actually might not be a bad way to go. That is, if Medarex can show this treatment is safe faster in inflammatory bowel disease, then we can take it to a phase 2 clinical trial in SCI faster. Reeve-Irvine Research Center is already working on ways that we can take this into SCI as quickly as possible as we believe it will have an enormous impact on the recovery of people with new injuries.
Enhancing the growth and regeneration of damaged nerve cells
In humans, during development, there is massive neuronal growth. Once functional connections are made, this growth is shut off by a variety of inhibitory mechanisms that prevent the nervous system from growing out of control. The problem is, after a spinal cord injury, these inhibitors stop nerve cells from regrowing. The stop signs that are so important in normal development become a major roadblock to regeneration. Scientists have long recognized that the environment of the CNS, the brain and spinal cord, is inhibitory for regeneration, and that Nogo, a small protein made by myelin (the insulation that wraps around axons and allows neurons to send electrical signals) is a part of the inhibition story.
Dr. Oswald Steward, RIRC Director, is looking at the role of Nogo by examining animal models that do not have Nogo. We do not know of existing animals that lack Nogo, but we can make them through a process called transgenics. We know a great deal about the mouse genome and can manipulate it to add specific genes, knock-in models, or remove specific genes, knock-out models. Several research groups have generated different mouse models that change the Nogo gene, and interestingly, the different models show mixed results, with some showing no regeneration, some showing a little regeneration, and some showing robust regeneration. Dr. Steward is looking to understand the difference between these models and to better understand the role of Nogo. His research is targeting ways to improve the regeneration seen when the stop signs are removed.
The development of a single drug is estimated to require over $1 billion and 10 years, and the majority of therapies fail along the way for a variety of reasons, including safety, efficacy, or impracticality. Dr. Os Steward has begun a Roman Reed supported project that could bypass many years of pre-clinical testing and safety trials and save hundreds of millions of dollars.
Pharmaceutical companies often test many forms a drug, only one of which might end up in your medicine cabinet. The others might be safe in people, but for whatever reason, are not what the company is looking for and so they sit on a shelf in the company lab. These FDA approved therapies represent a fantastic opportunity. Through a relationship with a pharmaceutical company, Dr. Steward has access to 7 of these drugs and will be testing them in rats with chronic, cervical spinal injuries. These particular drugs were singled out for SCI testing because they are neuroprotective in a fish model of neural injury.
If one of these already FDA tested therapies proves useful for spinal cord repair, even if it was original developed to prevent hair loss or erectile dysfunction, a clinical trial could begin in a matter of months.
The enormous potential of the general strategy of testing FDA approved therapies was demonstrated by a recent study in which over 1,000 potential drugs were tested to see if they prevented motoneuron degeneration in vitro (see Anatomy 101 for some definitions). Agents with positive effects in a dish were then screened in an animal model of ALS (Lou Gehrig's disease), a devastating disease where people slowly lose the ability to control their muscles because of motor neuron loss. This screen led to the discovery that certain antibiotics in use for other indications have a completely un-expected neuroprotective effect. The initial discovery was published in January 2005, and it was then possible to immediately plan a clinical efficacy trial for ALS patients for 2006.
Dr. Steward plans to capitalize on this approach and will screen drugs that are already approved by the FDA for use in humans or that are in a late phase of development for other applications. Therapeutic efficacy of these drugs will be tested in well-characterized animal models of cervical SCI that assess the kind of forelimb motor functions that are important for people (forelimb and digit use).
An approach involving screening of FDA approved drugs offers the potential of bringing a basic discovery to an initial clinical efficacy trial (phase II human clinical trial) within MONTHS rather than years after the initial discovery of therapeutic efficacy in animal models.
Dr. Keirstead is using a different approach to neural regeneration. He is a myelin expert. Myelin is the insulation in the central nervous system that allows neurons to send electrical messages. He has developed several different lines of research looking at degeneration and regeneration of myelin. One project involves a novel immunological technique for temporarily removing myelin from discrete areas of the spinal cord. Dr. Keirstead has used his innovative technology, on which he holds a patent, to show that it is possible to promote axon regeneration in the spinal cord of experimental animals by temporarily removing myelin. Once the axon has grown through the injury to its pre-trauma site, the myelin can be regenerated allowing restoration of function. However, you still have the problem of the fluid filled hole that the axons must cross. To deal with this, Dr. Keirstead transplants Schwann cells, myelin makers of the periphery, into the cavity to act as a bridge.
A second tissue transplant approach by Dr. Keirstead is with human embryonic stem cells. Embryonic stem cells have the ability to become any of the body's cell types, and so offer tremendous promise for treating many diseases and injuries with cell replacement. Dr. Keirstead is working in collaboration with Geron of Menlo Park, California. Geron owns several of the federally approved human embryonic stem cell lines. To be therapeutic, embryonic stem cells must be told what to become. If you transplant pure stem cells into a spinal cord injury, you will get a tumor. The stem cells must be pre-differentiated. That is, you must tell the stem cells what you want them to become before you transplant them. For SCI, we need central nervous system cells, neurons, astrocytes and oligodendrocytes. Dr. Keirstead was the first to figure out how to turn human embryonic stem cells into oligodendrocytes, the insulation makers of the central nervous system. Not only can he make human embryonic stem cells turn into oligodendrocytes, he can make high purity population, where 98% of the stem cells turn into myelin makers. This means that when these cells are transplanted into a spinal cord injury, we know exactly what they will become. To take this type of therapy to humans, this is essential.
Over the past couple of years, Dr. Keirstead has been working out the best model for using the cells for SCI repair. When these cells are transplanted into a rat with SCI 7 days after the injury, the transplanted cells turn into myelin makers and they wrap up nerve cells that have lost their insulation. These cells show all the chemical markers of normal oligodendrocytes and have the correct anatomical appearance. These cells also seem to be functional. Animals that receive the transplants show better walking 2 months after injury than animals with the same injury and no transplant. The walking is not perfect, but it is significantly better. Based on these exciting results, Geron and Dr. Keirstead are working hard with the FDA to get this to clinical trial in humans.
Dr. Keirstead has also tried this therapy in a chronic situation. Rats with 1-year-old injuries (given that rats only live about 2 years, that's an old injury) do not show improved walking when given oligodendrocyte stem cell transplants. We think we know why though - scar. A long-term, or chronic, SCI has a tremendous amount of scarring. Dr. Keirstead has found that the scar is not just around the injury site, but also around individual axons, the part of the nerve cell that sends messages. Members of his group are now focusing specifically on the scar with the goal of removing or penetrating it to allow for repair.
A third tissue transplant approach by Dr. Keirstead uses olfactory ensheathing glia, or OEGs. OEGs normally support the regeneration of olfactory neurons (smell neurons), which are the only central nervous system neurons in adult humans to regularly regenerate. Dr. Keirstead has transplanted rat OEGs into rats and is now using human OEGs transplanted into rats as the next step toward treatments for humans. The National Institutes of Health had been waiting for over 5 years to give a store of pure human OEGs to a scientist with a far reaching and forward thinking research program. Dr. Keirstead, it turns out, is the scientist they were waiting for. He has successfully grown the human OEGs in culture, no mean feat in itself, and is now transplanting these cells into rats with SCI. Preliminary results indicate that animals with these transplants recover function better, and there is a suggestion that OEGs may play a role in bring bladder function back faster.
Dr. Aileen Anderson is using yet another approach. She is working with Stem Cell, Inc. using their human neural stem cells. Unlike the embryonic stem cells, which have to be told what to become, these cells already know what they want to become - central nervous system tissue. Rather than forcing the stem cells to become a specific type of cell, like Dr. Keirstead's oligodendrocytes, Dr. Anderson is transplanting the neural stem cells into a SCI in mice and letting the cells decide what to become and where to go. When transplanted a week after injury, the neural stem cells migrate around the injury site and become a mixture of neurons, oligodendrocytes and astrocytes. Moreover, the mice that received the cells after injury recover walking better than animals with the same injury and no transplant. Dr. Anderson and her team are now looking to understand what signals make the stem cells become one cell type or another and how this might be used as a therapy.
Improving Motor Recovery
Much of SCI research focuses on recovery of walking, but to those with quadriplegia, hand function is desperately important. Dr. Kim Anderson has been working on ways to measure hand function in a rat model. Researchers rarely use cervical injuries, which cause quadriplegia. As with humans, animals with cervical injuries are often compromised to a degree that self-care becomes impossible. However, Dr. Anderson has developed a model where specific aspects of hand function, fine motor control and grip, are lost or reduced after injury, but the animal is otherwise completely functional. When asked to do certain specific tasks, the rats show deficits, but otherwise you can't tell them from uninjured animals. We now can use this model to assess various treatments on recovery of hand function.
Rehabilitation is another very important component of SCI research and functional recovery. Center Associate Dr. David Reinkensmeyer, an aerospace engineer, is developing robots for rehabilitation. He is specifically interested in the area of biomechatronics, or the use of intelligent electromechanical systems to diagnose, treat and support affected functions of the human body. He and his team have developed a robot that helps to retrain arm movements. The device supports the arm and basically removes gravity. Video game like tasks are used to repeat different movements, strengthening muscles and neural connections.
Dr. Reinkensmeyer is also collaborating with researchers at California State University at Los Angeles and UCLA to develop a robot that would coordinate step training. Researchers at UCLA have found that the spinal cord below an injury can remember how to walk or stand, but it must be retrained to do so. Animals with spinal cord injuries can learn to walk on a treadmill, and humans can also. While injured individuals can not walk on their own, with body support and therapists or, even better, robots moving their legs, they can begin to retrain their muscles and nerves to produce walking movements. This may be very important for keeping an injured individual's body ready for when treatments become available and further data suggests can help improve what function is left after injury. In addition to developing robots for human treadmill training, Dr. Reinkensmeyer is also creating ones for rats and mice to be used in the laboratory.
Autonomic Function
Autonomic functions are bodily functions over which we have little conscious control. Bladder and bowel function, sexual function, pain, regulation of temperature and blood pressure are all autonomic functions. While paralysis is the most obvious result of SCI, according to a recent survey, people with SCI reported that return of bowel / bladder and sexual function would most improve quality of life. This survey was taken by Dr. Kim Anderson at the RIRC. Herself a quadriplegic, Dr. Anderson realized that there was a real disconnect between what SCI researchers were measuring and what was most important to people with SCI. Her data clearly showed that research on autonomic functions was most definitely needed and the research community has responded. Here at the RIRC, almost all of our experiments now measure pain and bladder function in addition to walking.
It may be that a treatment for bladder dysfunction or other autonomic functions is easier to develop than one for walking. Obviously, we'd want to get that to people as quickly as possible to improve quality of life while continuing to work on locomotion and other components of SCI. Indeed, it may very well be that treatments become available in a piece meal fashion, with scientists finding answers for different aspects of SCI with different types of treatments. These would eventually form combination therapies addressing all aspects.
Models and Techniques
In order to find treatments for spinal cord injury, researchers need good tools. These tools allow us to ask questions like did the treatment result in better functional recovery, is a specific molecule responsible for blocking regeneration, and which cells survived after transplantation. Tools include the correct animal models. Rats and mice are excellent animal models for spinal cord injury research. Rats have much the same physical response to injury that humans do, and we know a great deal about mouse genetics and so are able to manipulate their genes to ask all manor of questions. In addition to models, research tools also include techniques that allow us to ask new questions, examine problems in a new way, or get information that was previously inaccessible. Development of such tools is an essential part of spinal cord injury research and will play a critical roll in all treatments. The Reeve-Irvine Research Center is actively involved in developing new models and tools to find answers to the SCI research puzzle.
SCI research has brought us to a place that no one imagined even 15 years ago. We have learned an astounding amount about spinal cord injury. There is still much we have to learn. We still don't have an instruction manual for the spinal cord, but we are getting closer to understanding what happens to the body hours, days, weeks, and years after an injury, and discovering ways that we can repair the damage. The field is currently on the threshold of major discoveries that will lead to new treatments for neurological dysfunction brought about by injury, stroke, degenerative diseases, and developmental and genetic disorders.
Please feel free to contact me any time.
Best wishes,
Maura Hofstadter
