AVANCEES ET DEFIS DE LA RECHERCHE SUR LA MOELLE EPINIERE EN 2014 ET 2015
Fevrier 2015 – La version française de cet article sera disponible d’ici peu.
Ecrit par Corinne Jeanmaire, pour la fondation EndParalysis. Remerciements Ruth Purves and Chris Powell.
The purpose of this post is to provide a summary of the important developments and spinal cord research progress towards recovery. In line with the scope and focus of the EndParalysis foundation, we will mainly focus on research applicable to chronic spinal cord injury and therapies that are at clinical or pre-clinical stage and thus have a potential to be applied successfully on human patients. We have noted some interesting progress in 2014 and can see exciting prospects for 2015 and the coming years. The list below is far from exhaustive but is simply meant to give an idea of the momentum currently at play. Is it a cure? No, none of those projects are “the cure” yet, but many of them have the potential of bringing small to significant functional recovery to the patients, either applied in isolation or in combination with other therapies.
Never before was the potential for functional recovery after SCI so high. The question is now how to accelerate the move. The awareness of the need for more spinal cord injury research, the financial means given to it as well as an increased international collaboration are still, and more than ever, key to quicker and bigger progress. In that respect we will also look at the research advocacy environment and highlight some interesting initiatives by some of the larger SCI foundations and come back to the role and the uniqueness of the EndParalysis foundation in that context.
A. KEY AREAS OF RESEARCH AND THERAPIES (not by order of relevance) 1. EPIDURAL STIMULATION/ NEURO-MODULATION
E-stimulation has come up many times in the news in 2014 and has generated quite some hype. Is it a cure for spinal cord injury? No, by far not (based on data published so far) but it might become a nice add-up to current rehabilitation techniques, especially for incomplete injuries. It might also be combined with regeneration approaches in the future, to strengthen functional returns. We are now going to highlight the various types of e-stimulation currently under development.
1.1 Dr Harkema – University of Louisville, Kentucky– Christopher Reeve Foundation
By April 2014, four spinal cord injury patients had been surgically implanted with electrical stimulator units. The devices are placed over the lower part of the spinal cord and send electrical impulses, to activate the lumbar circuitry.
According to the publication, (For more info click here), 2 patients had a motor and sensory complete injury (ASIA A) whereas 2 patients had a sensory incomplete injury. After some physical training, patients were able to stand up and take steps when the stimulator was on. Is this a full recovery? No, it is important to understand that the movement of the limbs is only possible when the stimulation device is switched on and that the function is not sufficient to have people really “walking”, even though they can now move their legs on command. Nevertheless, and this is the most interesting aspect of the study, these patients have all reported to have obtained some significant autonomic recovery. That includes bowel, bladder, sexual function and temperature control. This data was unfortunately not published nor documented, it is therefore difficult to assess whether we can merely speak about a slight improvement or a full control, which would be fantastic progress. It is the goal of a clinical trial expected to enroll patients as of September 2015 to check and document those findings on a bigger number of patients (36 people). For more data see The Big Idea project sponsored by the Christopher Reeve Foundation.
1.2. Dr Reggie Edgerton, UCLA. NRT (NeuroRecovery Technology)
Reggie Edgerton’s work forms the basis for most of spinal cord stimulation projects carried out today. Edgerton’s group and a private company he has formed (NeuroRecovery Technologies) have been working with a noninvasive epidural stimulation device; the fact that it is transcutaneous (through the surface of the skin), and therefore noninvasive constitutes a major difference versus the strategy currently pursued by Dr Harkema. Current devices have been applied on the upper body in order to improve or restore upper extremity functions. The results have been said to be quite remarkable, but have not yet been published (in his presentation at the Working2Walk 2014 congress, Dr Edgerton mentions 6 quadriplegic patients regaining significant functions.). This team is also raising funds for future clinical trials. More info here.
1.3. Dr Gregoire Courtine, EPFL Switzerland
Although Gregoire Courtine’s work has so far only be applied on animals with acute injuries (i.e. after a few hours or a few days after the injury), it is worth mentioning since it belongs to the same family of spinal cord stimulation, but Dr Courtine does combine electrical stimulation with the use of a chemical cocktail to get results. Through this double strategy, rats with an acute spinal cord injury have been shown stepping on a treadmill. It is hoped that a human size version of the system could be used in robot-assisted rehabilitation for patients with incomplete spinal cord injuries. The researchers want to test their scaled-up system, called Gait Platform, in human trials as early as next summer.
2. SCAR REDUCTION THROUGH ENZYME OR PEPTIDE
2.1. Chondroitinase and gene therapies – Dr Elizabeth Bradbury (King’s College London), Dr Elizabeth Muir (University of Cambridge), Prof Joost Verhaagen (Netherlands Institute for Neuroscience), Dr Rafael Yáñez-Muñoz (Royal Holloway, University of London) and SPINAL RESEARCH
One of the biggest issues preventing recovery after a chronic spinal cord injury is the scar that appears a few days or weeks after the injury and prevents any axon from growing away from the lesion area. The application of a bacterial enzyme called chondroitinase, or Ch’ase, has repeatedly been proven to degrade the scar, to promote growth and to improve recovery in animal experiments. Now, it’s high time we switched to human application. However, applying it on people is challenging. The goal of the project “CHASE-IT”, initiated by the International Spinal Research Trust (ISRT), is to make the Ch’ase therapy ready and safe for clinical application. It relies on an international collaboration between various researchers, among others in the UK and in the Netherlands. Recent experiments, using gene therapy models to deliver the enzyme, have moved the therapy closer to human application. CHASE-IT is the first research project co-financed by the Endparalysis foundation, because of its high potential and its clinical relevance for chronic SCI patients. We are currently raising funds for it. More info about the overall program here: and: here.
2.2. Peptide and Ch’ase – Jerry Silver- Case Western University.
It is not possible to write about Ch’ase therapy and about scar degradation without mentioning Dr Jerry Silver’s work. Dr Silver has shown remarkably consistent recovery of breathing and bladder function in chronically injured rodents by using Ch’ase in combination with nerve graft. Besides, he was also able to show some good recovery in ambulation of acutely injured rats by using a peptide that he now plans to combine with Ch’ase, with e-stimulation and growth factors. You can view his presentation during the 2014 Working2Walk congress, here.
3. CELL THERAPIES (and combinations)
3.1. Stemcell Inc – Pathway study –
The company Stemcell Inc has been carrying out a safety study (clinical trial phase I) treating 12 chronic spinal cord patients with their neural stem cells (in Switzerland and Canada). The first results showed that the therapy was safe and it also showed some light sensory improvements for some patients. The Pathway study, which is an expansion of the earlier trial, is a Phase II clinical trial and will test the safety and also efficacy of neural stem cells in chronic cervical spinal cord injury. The trial treated its first patient at the Miami Project and 52 patients are expected to enroll. More information here.
3.2 Neuralstem inc – Neural stemcells
A clinical trial started in the USA in October 2014, sponsored by the biotech company Neuralstem, primarily to check the safety (and later-on the efficacy) of neural stem cells on chronic spinal cord injury patients. What’s the expected mechanism? “To return meaningful function to the patients, existing nerves from above the injury will need to traverse and connect to the intact area below the injury, which we believe can happen via our transplant. The new nerves generated from the transplant itself can connect to the host cord above and below the injury and contribute to the rebuilding of the damaged circuitry, as demonstrated in animal studies (Lu, Gorp)” – See more here.
3.3 Dr Wise Young- Umbilical Cord blood stem cells + combinations In the fall of 2014, Dr Wise Young, Rutgers University and SCINetChina, presented some preliminary information from the Umbilical Cord Blood & Lithium Phase II clinical trial that has taken place in China. He explained that although none of the chronic ASIA A participants had improved motor scores, 15 out of the 20 patients were able to take steps with a walker whilst in rehabilitation. It is useful to mention that the trial also included a very specific and intensive physical rehabilitation item, in addition to the cell and lithium therapy. In the videos presented by Dr Wise Young, we could see some people walking with a walker and without any braces to support their legs. However, none of those patients showed improved motor scores (meaning that they cannot contract any individual leg muscle on command). So how can they “walk”? Is this walking ability merely due to their intensive locomotor training (and thus activation of the so-called “central pattern generator”) or is it more than that? Can it become functional or will it remain therapeutic walking? A lot of questions remain and further studies are planned (including in the USA). In the meantime we eagerly await the publication of the trial data. You can view a part of Dr Young’s presentation during 2014 Working2Walk symposium, here.
3.4 Nose cells and nerve graft – Pr Raisman (UK) and Dr Tobakow (Poland) In October 2014, in Poland, a paralyzed man was reported to get recovery after some of his nose nerve cells (these were actually taken from the olfactory bulb deep in his brain) were transplanted into his spinal cord and some peripheral nerve tissue from the patient’s ankle was grafted to serve as a bridge over the lesion. He went from complete paraplegia to incomplete (Asia A to Asia C). We welcome this positive and promising development, even though it should be highlighted that this is only ONE patient, with a very particular lesion pattern (his spinal cord was clear-cut and the lesion was very “clean”. Most injuries are much more “messy” and involve some level of contusion of the spinal cord). His progress is real though, and the science behind is solid. The patient is not (yet) really “walking” unlike what most media reported (from the CNN video we can see that he is actually moving by using the strength of his upper body with the help of a walker and his legs are supported by long leg braces. This is a therapeutic exercise for many paraplegic people and is not functional). However, the scientific details published by the team of Pr Raisman do show some interesting level of functional recovery (the patient has recovered some level of muscle control in his legs, meaning that he can contract them willingly), some return of sensation, and imaging seems to indicate that axons grew and found their way to targets, both up and down the cord. This is very significant progress for the patient and an interesting scientific development. A trial involving 10 patients is currently in preparation and we are looking forward to seeing the results! Here is a link to the published data.
B. ADVOCACY AND RESEARCH ENVIRONMENT
What does the above overview tell us? It does tell us that a level of functional recovery after a chronic spinal cord injury is becoming a realistic endeavor. In the meantime, a lot of work remains to be done. The potential of spinal cord injury research is becoming bigger and bigger but we all need to enable this potential through our active and targeted support. Only then can functional recovery after spinal cord injury become a reality.
In addition to scientific developments, we also welcome a few initiatives from various foundations that are trying to attract more global attention and funding towards spinal cord injury research (for example, the Wings4Life ‘World Run’, in its second year now with all proceeds going to research).
Unite2FightParalysis (u2fp.org), in the USA, an organization driven by patients or patient relatives carries out remarkable work towards giving access to spinal cord injury research progress data through their Working2Walk Congress every year and through their video database. This organization also brings their SAB to the disposal of any smaller organization that would like to assess the scientific potential and seriousness of a given project.
We also welcome the more integral and goal-driven approaches now taken by some organizations. This is the case of Spinal Research in the UK, who took the initiative of setting up a program to make the very promising Ch’ase therapy ready for human trials while it had remained stuck in the labs (pre-clinical stage) for too many years.
We also see the need for international collaboration and the need for more goal-driven approaches. That is the principle behind the “CPN Challenge” recently launched by the Conquer Paralysis Now (CPN) Foundation. The CPN Challenge program plans to award nearly $20 million in grants and prizes over the next ten years. The idea is to incentivize researchers to find a solution to chronic spinal cord injury by offering strategically designed prizes, fostering collaboration through competition and attracting the best scientists and engineers into the field. See more information here.
We, EndParalysis foundation, are a small but goal-driven organization. One of our concerns is that funds raised by organizations, among others from patients themselves, with a promise of bringing those patients closer to a cure, are indeed used in an optimal and an honest way. It does mean that these funds are indeed spent on therapies that have a chance to be applied successfully to patients in a chronic setting. Science is complex and we cannot foresee the results of experiments nor promise success. Therefore nobody can promise a cure. But we can at least promise to genuinely act towards it! We have seen too many organizations raising money on behalf of the so-called “cure” and allocating it to a totally different area, for example “quality of life” which has nothing to do with functional recovery or cure! That is the reason why we commit to a 100% transparency as to where our funds are going (i.e. projects targeting the human translation of therapies for spinal cord regeneration and functional recovery after chronic SCI). We also commit to spend 100% of your donations on research since we personally finance the costs incurred by running the foundation.
Besides, we also believe in working together. Rather than reinventing the wheel, we aim to work with existing bigger organizations; leverage their resources, add up value for them and for the field through co-financing some of their promising projects, but also keep the “big picture” and the end-goal in mind by connecting the dots and ensuring, as much as possible, a collaborative and goal-driven approach. There is a need for accelerating the process that will lead patients to some level of recovery.
This acceleration will not happen unless more people (including researchers, scientists and patient organizations) work together toward one single goal: offering some level of real functional recovery and ultimately a cure to patients.