PROGRESS AND PROSPECTS OF CHRONIC SPINAL CORD INJURY RESEARCH IN 2015 AND 2016

March 2016 – Update May 2016
Written by Corinne Jeanmaire, for the endParalysis foundation and for the ESCIF (European Spinal Cord Injury Federation) Research Group. With thanks to Harvey Sihota and Chris Powell for their input and to Beverley Saunders for her editing support.

The purpose of this article is to provide a summary of the important developments in spinal cord research 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 on 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 really interesting progress in 2015 and early 2016 and we can see even more exciting prospects for 2016 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. Do we have 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.

always impossible until itsdone moonNever before was the potential for functional recovery after SCI so high. Admittedly, we have been saying this for some time now. However, 2015 and the beginning of 2016 really show an evolution compared to previous years as far as the number of chronic spinal cord injury human trials and actual results are concerned. In 2015 it seemed as if more and more stakeholders, at least the bio-techs and pharmaceutical companies of this world, had decided to give chronic spinal cord injury the attention it deserves. After all, it is simple logic to concentrate on the biggest possible market, i.e. the spinal injury patients at chronic stage (basically everybody becomes chronic after just a few weeks post injury).

Also, certain limited but significant functional results have been reported and documented. Last but not least, a number of the planned clinical trials include various innovative and promising combination therapies.

In other words, the potential for a level of functional recovery after spinal cord injury is becoming more feasible than before. Full reversal of paralysis, however, still appears farther away and therefore raises the question: how to accelerate progression? We all know that a complete breakthrough is very likely to occur as a result of a combination of various therapies rather than from a single strategy. How can we create an environment, an eco-system to enable rapid identification and testing of promising combination therapies with the ability for direct application to humans?

We, the patients, patient organizations and charities have a role to play, in cooperation with all relevant stakeholders in this field. Being fully aware of the status of current research and trials is a first step. Therefore, we hope you will enjoy reading this article. If you get as excited by the progress as we are at the endParalysis foundation and should you decide to get involved, please contact us at Corinne@endparalysis.org. Any help or input is welcome. You may also donate here. Be the change, be the cure! You can make a difference! Thank you!

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Spinal cord injury research progress towards recovery in 2015: functional recovery after spinal cord injury will become possible.

1. REGENERATION: CELL THERAPIES (and combinations)
1.1. Stemcell Inc – Pathway study
Of the first six patients enrolled in the “Pathway study” (a Phase II clinical trial focusing on cervical spinal cord injury at chronic stage – see more info on the clinical trial here:  four patients have been reported by the company to show a pattern of improvements in both strength and motor function, six months post-transplant of the cells. These interim findings have not yet been subject to scientific (peer-reviewed) publication, but are, if confirmed, very encouraging. “The improvements in upper extremity muscle strength and function can be seen in specific tasks such as opening a jar, picking up coins or grasping and turning a key.” According to Stephen Huhn, CMO and Vice President.

Source: Investor Stemcellsinc

Very recently (March 2016), a number of significant improvements were also reported in the media regarding one particular quadriplegic patient who, according to the publication, would now be able to make his chair-bed transfer on his own; an impossibility before the stem cell transplant. This, however, is anecdotal and requires confirmation through a peer-reviewed scientific publication.

Pathway-Logo-640It is reported that all patients were treated between 10 to 23 months post-injury, a stage at which spontaneous improvement is almost excluded (contrary to the acute and sub-acute stages during which a partial or sometimes even complete functional recovery can happen independently of any treatment given to the patient, hence the difficulty of assessing the efficacy of a therapy at that stage).

On a side note, Stemcell Inc undoubtedly believes in the commercial value of their therapies since they have recently decided to fully focus the Company’s resources on its proprietary HuCNS-SC® platform technology for the treatment of chronic spinal cord injury (SCI). Read more here.

Update (early 2016): The trial treated its first patients at the Miami Project and is expected to enroll 52 patients in total. It takes place in the USA but is currently recruiting patients worldwide (cervical injuries only). More information on the trial: here.

Final update (May 2016): Unfortunately, the results obtained were not good enough to continue the study. As often is the case, bigger investment would be needed which Stemcell Inc.  cannot afford.

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1.2 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 of their neural stem cells on chronic spinal cord injury patients.
Four patients were enrolled and the last patient underwent the procedure in July 2015. All patients had a chronic (one to two years post injury) complete spinal cord injury (ASIA A) at thoracic level (T2-T12).

In October 2015, it was reported that the implantation of Neuralstem stem cells in the spinal cord injury patients had been safe and well tolerated. It is interesting to note that the same cells and the same procedure is applied to ALS patients. Those outcomes will be exciting to follow as well. See more at: Neuralstem

Latest update (early 2016): There is, as yet, no report about the efficacy of the procedure. We are looking forward to reading about possible functional or sensory improvement.

1.3 Combination therapy: Stem cells + Invivo scaffold
After its first clinical trial focusing on acute SCI (for which they have just reported some positive results, read more at Business wire Invivo), Invivo announced, end 2015, that they were going to focus their research efforts for chronic SCI on Bioengineered Neural TrailsTM.

Bioengineered Neural Trails are injectable combinations of biomaterials and neural stem cells (NSCs) delivered using minimally-invasive surgical instrumentation and techniques to create trails across the chronic injury site. “Our goal is to restore neuronal connectivity and thereby promote neurological recovery in people with chronic SCI,” said Tom Ulich, M.D., Chief Scientific Officer of InVivo. “Our minimally-invasive therapeutic approach is to bridge the spinal cord lesion at the time of implantation with a trail of NSCs delivered in an injectable and biodegradable soft, gel-like scaffold.”
More at: Invivo Therapeutics

Bio-materials-sidebarLatest update (early 2016): Invivo is currently preparing a clinical trial along these lines. It is not yet known when the clinical trial will start enrolling patients, as the trial needs to undergo FDA approval first, which can be a lengthy process.

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1.4 Combination therapy: autologous neural stem cells and regeneration matrix – New World Laboratories, Inc and Novagenesis foundation
Another exciting combination was presented at the Working2Walk symposium in September 2015, by Jan-Eric Ahlfors, PhD, New World Laboratories, Inc. and CEO of Novagenesis Foundation. The combination therapy uses both a regeneration matrix and a neural stem cells transplant (placed within the matrix). It is noteworthy that those cells are autologous, i.e. coming from the patient’s own bone-marrow, which avoids auto-immunity issues. Those adult stem cells are reprogrammed into neural stem cells. Neural stem cells are the type of cells that are found in the central nervous system. It is thus natural to believe that they can contribute to regeneration of a damaged spinal cord.

Jan-Eric Ahlfors presented the concept of Novagenesis technology as well as some interim results and videos from a human clinical trial that took place in Moscow in Russia and involved four chronic spinal injury patients. Some level of functional recovery seemed to be visible in a few of the patients but has not been clearly documented yet. However, charts and electrophysiological exams did show positive changes in muscle activity and sensation, which is very encouraging.…spinal cord injury research for cure – treatment  – curative therapies – spinal cord research –

1.5 Nose cells and nerve graft – Pr Raisman (UK) and Dr Tobakow (PL)
In October 2014, in Poland, a paralyzed man was reported to have gained 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). Here is a link to the published data.

Latest update (March 2016): The patient’s so-called walking skills were, to be honest, far from impressive. However, the BBC recently published a video showing the same patient riding a specially adapted tricycle, first in a gymnasium and then outside (which means more resistance). As far as we can see on the video, this is a real functional recovery which supports the fact that some muscle strength improvement had already been reported in 2014. This is a great news. Read more and watch the video on: http://www.bbc.com/news/health-35660621

polish patient biking
We are also pleased to read that chronic SCI patients are currently (starting March 2016) being recruited for a new clinical trial taking place in Poland. As far as we know, the clinical trial follows the same protocol as the one applied to the first patient, i.e. extraction of olfactory cells from the olfactory bulb in the patient’s brain, transplant into the spinal cord (the spinal cord must be clear cut, not contused) and a peripheral nerve graft. The candidates for this clinical are required to spend several years in Poland as the procedure will be preceded and followed by an intensive and lengthy rehabilitation process.

Moreover, another clinical trial is in preparation, in the UK, following a slightly different protocol (the source of the olfactory cells might be different) and other patient selection criteria.

1.6. Schwann Cells clinical trial – Miami Project
The Miami Project launched their new Schwann Cell clinical trial for chronic spinal cord injury patients in February 2015. The clinical trial aims to establish the safety and efficacy of the Schwann cells in promoting the repair of the injured spinal cord at least one year post- injury. The transplanted cells are autologous (coming from the patient himself). We look forward to hearing more as the trial progresses.

miamiproject logo

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Latest status (March 2016): This study is still recruiting patients. Ten patients are expected to be enrolled in total. More details about this clinical trials and about selection criteria can be found here.

1.7 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 had 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 the aid of a walker whilst in rehabilitation. You can view a part of Dr Young’s presentation during 2014 Working2Walk symposium, here. To our knowledge, no new information has been presented in the meantime.

Latest update (early 2016): A lot of questions remain as to the extent of functional recovery obtained (is it functional since the motor score of patients has not improved?) and the source of the changes shown in patients (the combination of stem cell transplant with an intensive physiotherapy regimen made it difficult to identify the source of improvement). Unfortunately, to-date there is no peer-reviewed publication regarding this clinical trial. To our knowledge, Dr Wise Young is still working towards getting the study published and is raising funds for carrying out a similar clinical trial, this time in the USA.

…spinal cord injury research for cure – treatment  – curative therapies – spinal cord research – spinal cord injury research breakthrough…

2. SCAR REDUCTION
2.1. Chondroitinase and gene therapy –  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)

chase-it logoOne 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.

Update March 2016:
Professor Verhaagen’s lab has now produced a viral vector that expresses Chondroitinase in a regulated way (when necessary it can be switched on and off, making optimal control of the timing and quantity of the enzyme achievable). The gene vector is based on the AAV (adeno-associated viral) vector which, already in clinical use, is reducing many safety concerns.
liz bradburryIn Professor Liz Bradbury’s lab (Kings College, UK), the vector is now being tested on rats with clinically relevant spinal cord injuries to check the treatment’s feasibility and effectiveness in vivo. The next step will be to test the therapeutic gene vector in injured rats at chronic time points to confirm potential benefits for patients with long-standing injuries and establish the best therapeutic window for the treatment. We are very much looking forward to that next stage.…spinal cord injury research for cure – treatment  – curative therapies – spinal cord research – spinal cord injury research breakthrough…

Spinal cord injury research progress towards recovery – spinal cord research progress towards recovery – treatment – therapies – cure – functional recovery – spinal cord injury research

3. ELECTRICAL STIMULATION / NEUROMODULATION
E-stimulation has surfaced many times in media in 2014 and 2015. It has generated a bit of a hype, but is it a cure for spinal cord injury? The answer is: “by no means” (based on data published so far) but it might become a suitable addition 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.

It is worth noting that evermore studies are involving electrical stimulation in 2015 and 2016, either in the lab or at clinical level (on patients).

3.1 Dr Harkema – University of Louisville, Kentucky– Christopher Reeve Foundation

By April 2014, four spinal cord injury patients received surgically implanted 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), two patients had a motor and sensory complete injury (ASIA A) whereas two patients had a sensory incomplete injury. After some physical training, patients were able to stand-up and take steps when the stimulator was activated. Is this a full recovery? Negative, it is important to understand that movement of the limbs is only possible when the stimulation device is activated and even though patients can move their legs on command, it is not substantial enough to be labeled as “really walking.” 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. Unfortunately, as this data was neither published nor documented, it is difficult to assess whether the outcome can be measured as merely a slight improvement or full control. The latter would mean fantastic progress.

e_stimulation4 patients

Update March 2016:

Another publication is now available here. The center has now performed epidural implants on a total of ten patients. The results have not been disclosed but there is positive communication that the response of the latest six patients is consistent with that of the first four. A clinical trial started in 2015 is currently recruiting (36 patients are expected to be enrolled in total). The University of Louisville manages a patient registry for all clinical research programs being conducted there, including epidural stimulation. To learn more and apply as a potential candidate for future spinal cord research please visit: Louisville neurosurgery form.

For more data you may also go to The Big Idea project sponsored by the Christopher Reeve Foundation.

Furthermore, another clinical trial involving epidural stimulation was announced (Feb. 2016) in Minnesota. The study will begin to take subjects with chronic injuries for human trial within the next few months.

3.2. 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.

Further to the experiments carried out at the UCLA lab, Edgerton’s group reported in July 2015 that five men with motor complete spinal cord injuries (two to six years after the injury) improved voluntary “locomotor-like” function. The experiments involved a transcutaneous (non-invasive) stimulator in combination with an oral drug already approved for anxiety disorders.

See the press release and video here and the scientific publication here. It is worth noting that the so-called “locomotor-like” movements obtained through this method are not functional since they are carried out without any weight bearing. It is, however, an impressive result given that it occurs without any surgery. This external stimulator, being developed by NeuroRecovery Technologies is expected to be complementary to the implanted stimulators currently tried by other groups. NRT is currently raising funds to be able to develop and organize a clinical trial.

3.3. Dr Gregoire Courtine, EPFL Switzerland

Over the past decade, Dr. Courtine’s team developed a pragmatic therapy that restored supraspinal control over refined leg movements after severe spinal cord injuries in rodents.

paralyzed-ratsSpeaking at the Working2Walk Symposium in Washington DC (September 2015), Gregoire Courtine presented the latest update on his own approach to neuromodulation. See video here:
Courtine’s lab is developing a wireless platform that would take advantage of a brain implant to decode an intent to make specific movements and use that information to deliver stimulation to the spinal cord to evoke the movement.

Latest Update (March 2016): G-therapeutics (a company co-founded by Gregoire Courtines, is developing two products: one is a fully dedicated implantable spinal cord stimulator, and the other one is a robotic rehabilitation platform. By enabling nervous system rewiring, the therapy is expected to help paralysed people walk again, especially if they have an incomplete injury. The approach has been successfully tested on fully paralysed animals and is progressing to human testing. Update April 2016: G-Therapeutics has raised € 36 million to develop its novel neuro-stimulation therapy for people with spinal cord injuries (SCI) . For more info click here.

…spinal cord injury research foundation for cure – treatment  – curative therapies – spinal cord research

CONCLUSION:

This article is far from exhaustive.

• It only includes a few of the ongoing or planned clinical trials for chronic spinal cord injury patients. Should you be interested in participating in a clinical trial, you may consult the lists established by U2FP here, or by SCOPE here, or make a search on www.clinicaltrial.gov. The above lists include all scientifically driven trials, both at chronic and at acute stage. Should you consider a therapy, remember that at this stage all therapies are experimental (without any guarantee of success). Also bear in mind that a legitimate, scientific clinical trial comes at no cost for the patient. Some pricey therapies you read about on the internet might be offered to you: they are what we call “unproven”/commercial therapies that are not peer-reviewed, do not contribute to general scientific knowledge and might, in some cases involve some additional safety risk. We do not endorse any clinical trial or any therapy in particular. However, should you decide to participate in an experimental therapy, we advise you to favor a clinical trial rather than an unproven/commercial therapy.

• Moreover, in the above article we have limited ourselves to a few key therapies which are applicable to chronic spinal cord injury and which are relatively close to clinical trial, or currently being tried on human patients. Some very exciting research is now taking place at basic or pre-clinical level. We have not included the various very promising projects, e.g. all studies aiming to comprehend and activate the neural locomotor network (to understand and stimulate the connectivity and neuroplasticity in the central nervous system). Also gene-therapies which are used as a very smart tool to express certain proteins in order to support regeneration or prevent nerve growth inhibition. This is not to mention the advances in the field of brain-computer interface, the bionic spine, which do not seem to hold the key to a full recovery but might also contribute in parallel to regeneration strategies.

 

The current scientific era has so much more potential on offer than before: Bio-technologies – gene therapies – stem-cells – 3D printing – Organs in a dish – Artificial intelligence – Big Data computing – SCI vision project.

act-as-if-what-you-do-makes-a-difference (1)If you haven’t started yet, it’s undoubtedly a great moment to support the movement towards curing spinal cord injury! Donate or get involved! www.endparalysis.org
Spinal cord injury research progress towards recovery – spinal cord research progress towards recovery – treatment – therapies – cure – functional recovery – spinal cord injury research

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