SCI research progress

Research overview

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 There is progress towards curing SCI

Significant progress has been booked in animal/ human studies. Various promising lines of research are highlighted below

Are treatments tested on humans?

There are more & more clinical trials worldwide. Our overview includes information about human studies ongoing or planned

When will therapies be available?

Most treatments are currently still experimental, but a positive sign is that more and more biotechs / commercial companies are created and invest into bringing promising SCI therapies to the clinic

Spinal Cord Injury research, therapies & treatments
Latest update: October 2023

Disclosure

This overview is exclusively focused on a number of key research projects or therapies towards recovery / cure after chronic Spinal Cord Injury. It is not meant to be exhaustive. Research focusing on acute injuries is not included. This overview is also in no way a recommendation for or an endorsement of any of these projects or clinical trials.

Theme 1: PREPARING the spinal cord to ENABLE repair

Theme 2: REGENERATING the spinal cord

Theme 3: RETRAINING the spinal cord

Theme 1:
Preparing the spinal cord to enable repair / regeneration

Latest update: October 2023

Reduction of the glial scar and neutralisation of the growth inhibitors so that repair becomes possible

Introduction:

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. One of the key scar reduction strategies involves using the Chondroitinase enzyme. Various peptides are also being tested for that purpose.

Additionally, this section also describes a few of the various therapeutic strategies that are used to neutralise growth inhibitors (often referred to as NoGo) after the spinal cord injury, and /or promote nerve growth.

ReNetX Bio – NOGO TRAP - COMPLETED (USA)

Background info:

The ReNetX a.k.a. “NoGo-trap” technology is expected to allow neurons to naturally re-grow by blocking factors that inhibit such growth. Contrary to the previously known “Anti-NoGo” technology, it is proved, as per the ReNetX company representatives, to bind and neutralise 3 types of inhibitors and is not limited to the NoGo-inhibitor. The intrathecal delivery of the NoGo Trap protein delivery has shown axonal growth associated with a certain level of functional by rats. It is reported to promote nerve sprouting and synaptic plasticity, as well as, to a lesser extent, axonal regeneration. Back in 2019, 2020 the ReNetX Bio company started a phase I-II  clinical trial  for  patients with an incomplete cervical injury  (info here June 2019, ReNetX Bio).

Latest update (August 2023):

In October 2022,  ReNetX Bio reported the results of the RESET Study of AXER-204 for Chronic Spinal Cord Injury. The results do include the apparition of biomarkers showing a biological effect. However, no sensitive or functional recovery was shown in any of the participants. More info here.

Patient enrolment/clinical trials:

This trial has been completed. More info on this trial can be found here: https://scitrials.org/trial/NCT03989440

 

Drug ES 135 (growth factor) – Human trial Phase 3- SUSPENDED (TAIWAN)

Background info:

ES135 is a recombinant human acidic fibroblast growth factor (rhFGF1) with 135 amino acids. With its effect to promote neurite outgrowth, ES135 can be applied to the medical use of repairing neuron function. The sequence of ES135 has been patented by Eusol-biotech in Taiwan, EU, China, and the United States.

Latest update (August 2023):

The human trial started in 2016 and was expected to last until 2024 according to clinicaltrial.gov. Unfortunately, the latter indicates that the trial has been suspended (update in April 2023. The reason included for this suspension is “low recruitment rate”. The patients recruitment criteria was not including whether the person should be at chronic or at acute stage of their SCI. If they wanted to focus on acute spinal cord injury patients, ie a few hours or days after their injury, it would explain why they could not recruit enough patients. Recruitment at the chronic stage of the injury is knowingly much easier and cheaper. We contacted the company to know more about this recruitment issue.

Patient enrolment/clinical trials:

160 patients with complete or incomplete SCI were expected to be recruited in Taiwan. However, the patient recruitment criteria was not precise and do not indicate if the therapy is applied at the acute or chronic stage. The trial was suspended in April 2024. More info: https://scitrials.org/trial/NCT03229031

 

CH’ASE IT: Chondroitinase and gene therapy for chronic SCI- PRE-CLINICAL stage (ANIMAL STUDIES - UK- NL)

Background info:

The application of a bacterial enzyme (a protein) called Chondroitinase, or Ch’ase, has repeatedly been proven to degrade the scar, to promote growth and to improve recovery in animal experiments. However, applying it to 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. The gene for Ch’ase is expressed in an active form in human cells and can be switched on and off to ensure an optimal and controlled delivery.

Latest update (Oct. 2021):

Two alternative gene delivery therapies have been developed/ are being tested :

a- The chondroitinase enzyme is delivered via a Lenti-virus vector (a virus made harmless and capable of carrying therapeutic genes). The consortium demonstrated this exciting new approach gave rise to improved walking and unprecedented upper limb function in rodent acute spinal cord injury models. See more information in this article and video and this Brain publication (August 2018). The same treatment was tested in a rodent chronic injury model at the end of 2018. The latest chronic trial has only shown modest results in terms of recovery and the current focus of the researchers is to combine treatment with rehabilitation to improve. More work has yet to be carried out to obtain the expected functional efficacy.

b- The Ch’ase enzyme is delivered via an Adeno-associated viral (AAV) vector which has the advantage of already being used in other human treatments and would, therefore, allow easier access to clinical trials. Various AAV vectors were created by Verhaagen’s lab and tested but they need further adjustment to ensure that the vector can be totally switched off when needed, without any further leakage. Indeed, one issue researchers found with AAV vectors was a noticeable background expression of the chondroitinase in the “off” setting.

The first two rounds of studies were co-funded by the endParalysis foundation and Spinal Research in the UK up to 2019. The follow-up studies are funded by the Wings for Life foundation as of 2020. The current study specifically focuses upon applying Ch’ase on rodents with a chronic SCI and combining with physio therapy to improve functional results.

 

Patient enrolment/clinical trials/ next translational steps:

-The AAV vector, once optimized, will be tested in both acute and chronic SCI models (rodents).

– Discussions are ongoing to test the best version of the chondroitinase therapy on humans. This is, however, a long-term goal. 

CRP (CSPG Reduction Peptide) – to reduce the scar at CHRONIC stage – Dr. Yu Shang Lee – Pre-clinical stage (Animal studies - USA & UK)

Background info:

The formation of an enduring glial scar near the injured site leads to poor nerve regrowth capacity and poor functional outcomes in chronic stages after SCI. Chondroitin Sulfate Proteoglycans (CSPGs) are the major components of this glial scar. The small peptide (a tiny organic compound) called CSPG Reduction Peptide (CRP) was designed by Dr. Yu Shang Lee’s lab (Cleveland Clinic – USA) to meet this need. The non-invasive character of the CRP (it can be applied by subcutaneous injection) is of great interest. CRP treatment, if proven effective, would in principle, be easily applied to human patients and might constitute a very valuable alternative to other scar-alleviating therapies currently under development such as Ch’ase. The endParalysis foundation and partners supported various animal studies to check the robustness, replicability and safety of the CRP therapy in order to advance it towards human trials

 

Latest update (October 2023):

  • 2022-2023 CRP replication + combination study (Ronaldo Ichiyama’s lab, Leeds, UK): This animal study was co-funded by endParalysis and partners in 2022. The experiment was meant to check whether the behavioural improvements seen by the animals treated with CRP could be replicated by another lab, and whether they could be enhanced by the electric stimulation of the cord. E-stim through an implanted stimulator has repeatedly been shown to (slightly or significantly) improve behavioural outcomes in a number of human subjects by “awakening” the spinal cord neural connections that had become “dormant” as a consequence of the injury.
    Unfortunately, the effect of the CRP peptide was not proven by this study: there was no significant difference between groups treated with e-stim only and the groups treated with E-stim+CRP.

  • 2020-2022 CRP dosing study (Yu Shang Lee’s lab, Cleveland Clinic, USA): funds were pre-allocated by endParalysis and partners at the end of 2019 for testing dose responses of CRP. The goal was to confirm previous outcome and to see if a higher CRP dose could lead to additional functional improvement, after chronic spinal cord injury. Dr Yu Shang Lee reports “We have demonstrated the efficacy of CRP treatment to repair chronic SCI by improving locomotion (in the first progress report) and lower urinary tract function. In anatomical study, we also showed the CRP treatment can reduce glial scars and enhance the sprouting of serotonergic fibers that may leading to the functional recovery”.

  • 2018-2019 rodent study (Yu Shang Lee’s lab, Cleveland Clinic, USA): after a first preliminary small study with a limited number of rodents, Dr. Yu Shang Lee’s lab carried out additional studies using more rats with a T8 chronic contusion SCI.  The project, co-funded by endParalysis in 2018, aimed to determine the efficacy of CRP alone, of ISP alone, and of CRP + ISP (ISP is another peptide, developed in Dr. Jerry Silver’s lab, Case Western Reserve University). Various tests were conducted, including a combination therapy. Starting two-month post-SCI, the treated animals received the various peptides by daily subcutaneous injection during three consecutive months. Both CRP and ISP were administered at a low dose in this study. The study showed that: 

    - CRP significantly improved bladder function and locomotor function
    -The results were not much improved or changed when adding up ISP
    -The test highlighted, on the other hand, that ISP alone did not enable any functional recovery of the rats at the CHRONIC stage (although it has been proven by Dr. Jerry Silver’s lab to have a robust effect at the ACUTE stage).

     

Patient enrolment/clinical trials/ next translational steps:

Over the period 2020-2023, endParalysis’ partner (Niall’s foundation - UK) funded independent CRO (Contract Research Organization) testing of CRP including pharmacodynamics (PD: studying the action of the drug on the organism) and pharmacokinetics (PK: studying the effect the organism has on the drug). These tests are necessary for any therapy advancing to human trials. The various in vivo and in vitro experiments carried out by the CRO have unfortunately failed to show a robust reach and effect of CRP when delivered subcutaneously.

However, a study carried out by  Dr. Brian Kwon (Canada) and funded by the DoD (Department Of Defense, USA) is currently testing the CRP in a larger animal model (mini-pigs with a T10 subacute spinal cord injury), using an intrathecal administration. We are looking forward to the results of the latter study. 

 

ISP ( Intracellular Sigma Peptide) / NVG-291– Dr. Jerry Silver/ NervGen biotech – RECRUITING PATIENTS (USA)

Background info:

Inflammatory damage to the spinal cord after the initial injury can continue to spread outward from the lesion epicentre into surviving tissue to cause further loss of function. The development of scar tissue encases the lesion core. Soon after the injury, the scar tissue, rich in inhibitory molecules, develops into a barrier to the regrowth of the injured axons. Dr Jerry Silver and his team at Case Western Reserve University have developed a molecule, known as intracellular sigma peptide (ISP) that helps regenerating axons ignore and bypass CSPGs (powerful inhibitory molecules in the scar). When ISP was administered non-invasively via injections under the skin, it was shown to lead to greatly improved bladder function and improved locomotion in animal models (rodents) with an ACUTE spinal cord injury.

ISP has been licenced by NervGen, a publicly traded biotech with the goal to take the therapy to the market to treat various neurological conditions, including spinal cord injury.

 

Latest update (August 2023):

In August 2023, NervGen announced that they have received approval to conduct a spinal cord injury clinical trial for ISP (a.k.a. NVG-291) involving both acute and chronic spinal cord injury patients. See press-release here.

The human trial includes both patients with an SUB-ACUTE (10 to 49 days after the lesion occurred) and a CHRONIC Injury (min 1 year, max 10years after injury).  A very important selection criteria is that patients have to have some remaining functions  CERVICAL INCOMPLETE  spinal cord injury (ASIA D or ASIA E). The trial includes a placebo group (a number of participants will thus not receive the full treatment).

Besides, a few additional animal studies had been previously announced:

– A rodent trial for acute injuries is ongoing, including a combination of NVG-291 + sub-cutaneous e-stim (electro-stimulation/neuro modulation of the spinal cord nerves, through the skin)

– A pig trial for chronic injuries has now started, carried out by the Candace Floyd’s lab (University of Utah, USA), in cooperation with various partners. The trial features a combination of therapies, i.e. the peptide and neuro-stimulation. 

 

Patient enrolment/clinical trials:

Nervgen is currently recruiting patients. To know more about the selection criteria, see this page:

https://scitrials.org/trial/NCT05965700

PNN-i study- Dr Kwok- University of Leeds- UK (animal study for SCI, but this drug is already on the market for other conditions)

Background info:

PNNi refers to a molecule that is already on the market (used to treat a rare disease). It was recently tested by Dr Kwok / University of Leeds, as a potential therapy for spinal cord injury. In her animal studies, the drug has shown promising results when used at the acute (i.e. very early) stage of SCI. The molecule seems to neutralise  the PNN (PeriNeural Net)  as well as the scar, which both prevent nerves regrowth. The main advantage of this therapy, if results are confirmed and the side effects are manageable, is obviously a shorter path to the clinics, since the drug is already approved.

Latest update (August 2023):

PNNi dosing study (including chronic SCI) by the Kwok Lab: this study was co-funded by the endParalysis foundation (2020-2022) together with two other foundations, i.e. the Marina Romoli Onlus (Italy) and  Gusu2cure (USA). The purpose of the study was to check the efficacy of the treatment at the chronic stage of SCI, and to determine the minimum dosage needed to reach a significant level of functional recovery. The study has proven that the molecule does indeed enable a clear functional recovery level in rats, even long after their initial injury, which is a very good outcome. PNNi molecule is used to treat people with a rare-disease and is thus suitable for clinical use. However, the latest study also showed that the dosage needed to achieve significant functional recovery in rats is higher than the one currently authorized on the market. Before going to human trial for use in spinal cord injury, it is necessary to finetune the treatment, either by increasing its efficacy so that it can be made effective at the authorized dosage or by addressing concerns of potential side effects and gaining regulatory approval for use at higher doses. 

Patient enrolment/clinical trials/next translational steps:

For Spinal Cord Injury, this therapy is still at pre-clinical stage, with a clear objective to go to the clinics. Various studies and optimisation of the molecule need to be conducted before it is tested on human subjects with a spinal cord injury. 

 

Other pre-clinical studies concerning scar reduction

Background info:

Scar reduction is an essential and critical challenge when it comes to treating chronic spinal cord injury. Therefore, many labs and researchers are currently working on the subject. Here, we simply give a non exhaustive list of  various pre-clinical studies.

Latest update (August 2023):

  • USA: Biomaterial + Ch’ase mRNA, localized delivery in rats with acute SCI. Bill Murphy, Dan Hellebrand. More info: here (publication, 2022)
  • UK: alternative delivery method for Ch’ase. More info: here
  • CANADA: alternative  delivery method for Ch’ase. Dr Molly S. Shoichet. More info here (publication 2017)
  • USA: Ch’ase direct delivery for non-human primates with SCI.
  • USA: Rose Bengal Study by Dr. A. Parr (University of Minnesota). See January 2018 publication 

 

Theme 2:
Regenerating/ Repairing the spinal cord

Latest update: October 2023

Repair/ neuro-regenerative therapies: (Stem)-cells, bio-materials / scaffolds / hydrogels, gene-therapy to restart axonal growth, growth factors/ molecules and/or combinations for functional & sensory recovery after a chronic spinal cord injury

Introduction: 

Spinal Cord Injury results in significant tissue loss and a number of strategies aim to replace and restore the cellular architecture in the hope to aid repair. This includes, for example, (stem) cell transplantation therapies, or transplantation of 3D bio-engineered tissue to replace/ repair damaged tissue/ nerves. It can also refer to gene-therapies with the aim of restarting axonal growth. These strategies can be further augmented by  combining with growth-factors or molecules to enhance neural regrowth and bio-material scaffolds to guide nerve regrowth. It can also involve other strategies encouraging neuro-regeneration and neuroplasticity (i.e. the remodeling of signals of the brain and spinal cord nerves). The list below is exclusively focused on treatments potentially applicable to chronic SCI, in line with the focus of our foundation and only covers a few of the numerous pre-clinical research projects worldwide as well as a few important planned or ongoing human trials aiming at a level of functional recovery. It is not exhaustive and in no way represents a recommendation for a given experimental therapy.

Adipose cells – Mayo Clinic – Clinical trial Phase II (safety+efficacy): RECRUITING PATIENTS (USA)

Background info: 

A first study was carried out on patients in 2019 to check the safety of mesenchymal stem cells (MSC) derived from fat tissue (autologous cells, i.e. from the patient him/herself) and to see if they could be safely administered into the cerebrospinal fluid (CSF) of patients with spinal cord injury. The trial had unexpected results on one patient with a chronic incomplete spinal cord injury. He had already recovered some functions but was still wheelchair-bound and had plateaued in his recovery. He gained major functions back after the Adipose-derived mesenchymal stem cells (AD-MSCs) transplant. More results about this particular case to be read here. It is to be highlighted that this is only one patient and that the other patients involved in the trial have not shown similar improvements.

Latest update (August 2023):

A new trial was launched in 2020 to check both safety and efficacy of the Adipose-derived mesenchymal stem cells (AD-MSCs) intrathecal delivery (i.e. through a puncture) on more patients with spinal cord injury, complete or incomplete. This trial is randomized, meaning that not all participants will get the same /full treatment. However the crossover design ensures that the people who first receive only physical training (control group – no stem-cells), will later on be given a single injection of stem cells (six months after their injury).

Patients enrolment (update August 2023):

This trial is still recruiting and is expected to deliver full results in 2024. From the selection criteria, it seems that this trial recruits patients who have had a certain level of recovery after their trauma, but who have now plateaued. For further info, go to  NCT04520373

Nose Cells (OEC’s) and Nerve Graft –Dr. Tobakow)- RECRUITING PATIENTS (Poland)

 

Background info:

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. Expectations of this study have to be tempered since we are now talking about a single patient. However, he went from complete paraplegia to incomplete (Asia A to Asia C) and has regained considerable functions.  Here is a link to the published data.  This study was pioneered by the late Dr. Raisman (deceased 2016).

 

Latest update (August 2023):

As far as we know, one patient had been recruited and operated upon in 2019, but the outcome of the treatment has not been communicated nor published. The clinical trial would follow the same protocol as the one applied to the original patient, i.e. extraction of olfactory cells from the olfactory bulb in the patient’s brain, transplantation into the spinal cord along with a peripheral nerve graft.  One more chronic SCI patient is still being recruited for this clinical trial taking place in Poland (Dr. Tobakow).   The Walk-Again website concerning this trial has not been updated for a few years but the Nicholls Spinal Injury Foundation communicated  some delays in their 2020 newsletter:” […] challenges faced by the Walk Again Project in Poland in 2019. The nature of the work means the project must adhere to EU legislation issued by the European Medicines Agency (EMA). In order to meet the strict criteria, new high-tech equipment and upgrades to the laboratory were required. All equipment has now been purchased; it is just the complicated work on the ventilation system that remains. This work is being carried out by the Wroclaw Medical University and as such is outside of our direct control”.

 

Patient enrolment (clinical trials)- update August 2023:  

In Poland: Only for patients with a transected /severed spinal cord.  The cord must be clear-cut, for example by a knife, not contused.  Also, the candidates for this clinical trial are required to spend several years in Poland as the procedure will be preceded and followed by an intensive and lengthy rehabilitation process. More info regarding enrolment is available here:  NCT03933072

It is not clear whether this trial is still ongoing or not. The website that was previously created to recruit patients is not online anymore, and the clinical trial page has not been updated since 2021. We sent Dr Tabakov an email asking for an update. Unfortunately, his email address also seems to be inactive and our email bounced back.

 

In the UK: complementary research on OEC’s – 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.  There is no public update available regarding this UK trial plan but it might involve acute injuries rather than chronic ones. One publication was made regarding the combination of OEC’s transplant with a biomaterial, and concludes the following (based on an animal study):
“Combination of OECs with biomaterials such as collagen increases the transplant size significantly without affecting the neural repair capacity of OECs. This improves the prospect of transplantation of OECs to bridge a larger surface area of injured spinal cord such as those seeing in human contusion injuries. Elongation of OECs guided nanofibers providing directional pathways may be more efficient in promoting regeneration of nerve fibers in spinal cord injury.” Read more here.

IPS* Stem Cells – Phase I (Safety) clinical trial ONGOING (Japan)

Background info:

In February 2019, Japan’s health ministry approved the use of induced pluripotent stem cells (*IPS). IPS cells are created by reprogramming cells from body tissue to revert to an embryonic-like state, from which they can develop into other cell types such as nerve cells. They are shown to have regeneration potential comparable to embryonic stem-cells but do not involve an embryo, hence being far less controversial. The ongoing human trial comes after experimental transplants into monkeys by Keio University professor Hideyuki Okano and others succeeded in restoring motor function so that the animals could walk. In a Sept. 2021 scientific publication, we learned basic information about the upcoming human. In January 14th, 2022, the very first patient is reported to have had the surgery and to be doing well. According to France24, “The patient will be monitored by an independent committee for up to three months to decide whether the study can safely continue and others can receive transplants”.

Latest update (August 2023):

From Keio University Hospital website: “In December 2021, Keio University Hospital became the first in the world to successfully transplant human iPS cell-derived neural stem/progenitor cells (iPSC-NS/PCs) into a patient with subacute spinal cord injury (SCI).  In an interview (May 2022) it is confirmed that this first trial will include four patients. 

 

 About the mechanism of action of the IPSc, Dr Okano says: “When we talk about “regeneration,” we are talking about making something “occur again.” By transplanting neural stem cells into the spinal cord, developmental events involving neurons, astrocytes, and oligodendrocytes can be repeated. In this way, we can do many things. We can reestablish interrupted neuronal circuits or supplement axons with glial cells and reestablish myelin sheaths. We can take once damaged skin, repair its structure, and restore its functionality.”

The researcher also mentions that the team also works on chronic spinal cord injuries and that they are developing a slightly different type of IPSc’s for that purpose.

 

Patient enrolment/Clinical trials:

This trial is not published yet in clinicaltrials.gov. Three more patients are expected to be recruited, two to four weeks post-injury. To our knowledge, only one patient has received the IPS cell transplant yet, and is currently monitored for safety (this small trial’s purpose is mainly to assess whether the treatment is safe).

 

 

Neuroplast (NL) – Stem Cells from Bone Marrow – CLINICAL TRIAL RECRUITING (Spain) & PLANNED (Denmark)

Background info:

Neuroplast is an independent company founded in 2013 and is located on the Brightlands Maastricht Health Campus in The Netherlands. A preclinical study showed that Neurocells, the product of Neuroplast obtained from the patient’s own bone marrow, significantly improved both locomotor functions and survival in rats with spinal cord lesions compared to rats treated with placebo (drug without an active agent). Source: http://www.neuroplast.com/. The research involves the transplantation of Neurocells and will take place in two different centers: Toledo (Spain) and Copenhagen (Denmark). The Neurocells are expected to have a positive effect both in terms of neuroprotection and neuroplasticity and thus to contribute to a level of functional return in both chronic and acute spinal cord injury.

Latest update (September 2023):

– Results from the Phase I trial (safety):  Neuroplast’s website confirms that the therapy has shown to be safe. It also mentions that “three patients [with chronic SCI] from their safety trial reported favourable effects. These include improved bowel control, sensory improvements and increased muscle tonus. One patient improved from a complete lesion to an incomplete lesion”.

– phase II/III (efficacy) trial: In September 2023, the company reported that 16 patients had been treated and that the first results of the trial would be known in February 2024, with a full study completion expected in August 2024. “The intervention group received Neuro-Cells® in the sub-acute phase after sustaining trauma, with six months follow-up to their primary endpoints. The placebo group received a placebo at first but have been or will be treated with Neuro-Cells® after the initial six-month follow-up period”

Patient enrolment/clinical trials:

The Phase II trial (aiming to check efficacy), involving people with a traumatic acute / sub-acute spinal cord injury (6-8 weeks after lesion) has started in Spain. It is not yet recruiting in Denmark. The clinicaltrials.gov website indicates that the trial is still recruiting, but it is unclear whether and when the Danish center will start recruiting participants. More info on NCT03935724.

Chronic SCI:  at this moment we do not know if another specific clinical trial will be organized for patients with a chronic spinal cord injury. However, it is interesting to highlight that the trial that just started will recruit patients in their sub-acute phase (6-8 weeks after SCI) but will also test whether the therapy works during the chronic phase. Indeed, the protocol is designed in such a way that the patients who are in the control group get a placebo (no stem-cell treatment) at sub-acute stage, but they do get the stem-cell treatment six months after injury. So, although chronic SCI patients will not be able to enrol this trial, it will nevertheless test the therapy at chronic stage thanks to this “early and late intervention cross-over design”. 

Dr. Wise Young- Umbilical Cord Blood Stem Cells (UCB) + combinations – Phase II CLINICAL TRIAL PLANNED (USA)

Background info:

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. The study has now been published in an open access journal, Cell Transplantation.  See abstract of the publication here.  A lot of questions remain as to the extent of “functional” recovery obtained (is it functional even though the motor scores of patients have not improved, meaning that they cannot contract any muscle on command?).  Also, the source of the changes shown in patients needs to be clarified (the combination of stem cell transplant with an intensive physiotherapy regimen made it difficult to identify the source of improvement).

 

Latest update (August 2023):  the latest information collected from CareCure forum indicates that Dr Wise Young is still raising money to make the trial happen in the USA and hopes to start in this fall (2023).  

In a presentation (Sept. 2021), Dr. Young indicated that the USA trial would now involve more patients (40 people) and include a control group (a number of patients who will NOT receive the stem-cell treatment). Another change compared to previous plan is that no lithium treatment will be included for any patient to simplify the protocol. The latter will only include the UCB stem-cells and/or the intensive physiotherapy.

The trial was expected to start in January 2022. However, it was announced that StemCyte, the company providing the stem-cells, pulled out of the USA trial. As a consequence, the team has to find a new source of umbilical cord blood stem cells and has  to go through the IND approval process from the beginning. The FDA is requiring an additional study to prove the new sources of cells are also safe and effective. 

 

Patients enrolment (update August 2023):

This study is in preparation and is not recruiting patients yet. These are the recruitment criteria as previously communicated (beware that they might have been adjusted): in order to qualify for this trial, you must have a complete injury between C5 and T11, be injured more than 1 year, 18-64 years old. There is no cost to participate in a clinical trial, but if selected, you would have to cover the cost of lodging and transportation in New Jersey (USA) for 6 months. For more info, email:  sciproject@dls.rutgers.edu

PS: the biotech company who pulled out of the clinical trial plan has actually launched their own clinical trial, and is currently recruiting patients in Taiwan. A USA trial location (in New Jersey) is mentioned in the trial data, but is not yet recruiting. More info here: NCT03979742

 

NC1 – Bone Marrow Stem Cells Intrathecal Injection- Late Dr. Vaquero – TRIAL PLANNED FOR INCOMPLETE SCI (Spain)

Background info:

Vaquero (M.D. Puerta de Hierro University Hospital, Spain) has been studying the impact of the autologous (from oneself)) bone-marrow mesenchymal stem-cells  (MSC’s) intrathecal injection (in the subarachnoid space). Various phase I/III trials have been carried out on both incomplete and complete spinal cord injury patients. More scientific details and detailed results can be found in the three following publications: 2016 publication (complete SCI) and 2017 publication (results for incomplete SCI). According to the latter publication, the latest Phase II trial has shown varying types of (quality of life or clinical) improvement in all patients and resulted in significant improvement in three out of the nine patients measured (those changed from respectively Asia A, B, C Grades to Asia B, C, D (i.e. becoming more incomplete). 

In 2019 the newspaper El Mundo indicated that  (translated from Spanish): “Today, after a long process involving a small group of people with this condition [SCI], they have announced the end of the development of a therapy [NC1] and its approval by the Spanish Agency of Medicines. Everything is ready to start working with 30 new patients [with an incomplete spinal cord injury]. They also reported that “The number of patients will gradually rise over the following years, in a process which is dependent on submitting regular reports and an assessment of the outcomes.”  

Unfortunately, Dr. Vaquero passed away in 2020 and it is not clear what the consequences are on the clinical trial planned earlier. Some information about the trials is available though, on the following page in Spanish.

 

Latest update (August 2023): 
We tried to get an update about the therapy and clinical trial that was expected to take place in Spain. Unfortunately, we could not find any relevant information. It looks like the clinical trial  might have been suspended, after Dr Vaquero passed away in 2020. 

However, a scientific publication  (October 2022) describes the results of administrating the NC1 cellular treatment to two patients with incomplete paraplegia. Both patients had met with a spinal cord injury after an operation treating a begign lesion in their spinal cord. Both patients had met with a spinal cord injury after the surgery, but they could walk before the stem-cell transplantation.  The publication highlights various improvements in the field of pain, ambulation and autonomic function after the NC1 Cells were transplanted intrathecally.

 

Patients enrolment (Clinical trials): 
There is currently no clinical trial  published on clinicaltrials.gov using the NC1 cell therapy for spinal cord injury patients.

 

"Dancing molecules" biomaterial scaffold - ANIMAL STUDY (PRE-CLINICAL STAGE- USA)

Background info (Nov 2021):

A scientific paper was published in 2021 featuring “Dancing Molecules” and their ability to “reverse paralysis”. The focus of the experiment was on rodents with a severe acute SCI. A video shows rats walking again 4-6 weeks after the injection (though their movement is by far not back to normal, so the term “reverse paralysis” seems to be overrated. The discovery, by Dr Samuel Stupp (North Western University) attracted major media attention. This “injectable therapy” is based upon “super-molecular chemistry” and nano-medicine (the injected material looks like water, but it contains nano-filaments/ nano-fibers and turns into a gel as soon as it touches the body cells). Super-molecules are an ensemble of thousands of molecules brought together. The injected molecules are also specially designed with signals. In the spinal cord, cells have receptors on their membranes and are constantly moving. So, the therapy is also designed to allow the injected molecules to move and follow the spinal cords cells. The researchers claim that the therapy have the following five effects (for rodents, in an acute SCI setting):

– regenerating axons after an severe acute spinal cord injury
– enhance vascular growth (blood vessels inside the cord)
– remyelinate the axons
– save a lot of motorneurons (necessary to enable movement)
– diminish glial scar.

Latest update (August 2023):

In January 2023, a new paper paper from Stupp’s lab was published. The in-vitro experiment described shows the advantage of combining his dancing molecules (the bio-scaffold) with iPSC’s (induced pluripotent stem cells, ie a type of stem cell made by genetically reverse-programming a human skin cell to become a neuron. 

In September 2022, during the U2fp symposium, Dr Stupp indicated that the rodent was already successfully replicated by another lab, in France. His own lab carried the study on mice and the French lab did it on rats with acute SCI. The same recovery level was observed. Hopefully,  the results of the replication study will be published soon. 

 What about the path to the clinic and chronic spinal cord injuries? In various interviews early 2022, Dr Samuel Stupp indicated that his goal is to test the therapies on humans. His lab has received a funding to prepare for the IND (application to the FDA to review and possibly authorise the therapy to be tested on humans) and to test the therapy in chronic settings. Since this treatment involves a really big number of molecules put together rather than a single molecule, it will be interesting to see how the FDA responds to this proposal. According to Dr Stupp, it is likely to be considered as one single molecule and should not face any issue. Another interrogation remains as to how the injection would be made into the human spinal cord. Would it be an injection through the dura (the envelop protecting the spinal cord)? Dr Stupp indicates that the matter has been discussed with various neuro-surgeons and that delivery strategy is the most likely.

Besides, Stupp informs that he is determined to test the therapy on chronic SCI as well, which is a good news. However, no timeline is known so far.

 

Patient enrolment/ Experimental trial- NOT YET:

The lab’s target is to go to clinical trial with the therapy. However, given the innovation level of the treatment, it can be expected that it will take quite some time to actually start human trials.

Mend The Gap - bio-materials platform for combination therapies - Basic/ pre-clinical research - UBC (Canada)

Background info (August 2023):

Mend The Gap is a very interesting approach to spinal cord injury repair. It takes into account the huge complexity of SCI and the need to leverage knowledge across various disciplines to develop a combinatory treatment. “Bringing together scientists, engineers, clinicians, translation specialists, and the spinal cord injury community, to address the grand challenge of repairing the spinal cord after injury”.

Latest update (August 2023):

To date, the biomaterial platform is still under development. It is not known whether a roadmap is available towards bringing a therapy to the clinics.

Patient enrolment/ clinical trial: 

The target of “Mend The Gap” is to accelerate research towards finding a cure for spinal cord injury through knowledge sharing. It is not know, at this stage, whether and/or when this will lead to a therapy and to human trials.

 

siFi2 therapy by MicroCures & USU University - Pre-clinical stage (animal studies- USA)

Background info:

The over-expression of FL2 (an inhibitory protein) after spinal cord injury results in inhibition to axon growth. Preclinical research suggests that siFi2 (a drug developed by the US biotech company MicroCures) can silence FL2 activity and thus trigger regeneration and reattachment of axons at the site of injury. This therapy is based on protein knock-down and enhances the body’s intrinsic healing processes. 

Latest update (October 2023):

Following the promising functional improvement observed in previous acute trials, endParalysis and partners have asked MicroCures and USU (Uniformed Services University of the health science – Maryland, USA)  to test the siFi2 therapy in rats with chronic injuries (endParalysis foundation co-funded this project through a research grant in 2021). The results of the study, as shared in October 2023, are encouraging. The experiment showed that the treatment is also effective at a later stage of the injury with improvements in both the BBB score (walking and stepping test for rodents) and the gait of the treated animals, when compared to the control group.

 

Patient enrolment/clinical trials/next translational steps:

This study is still at pre-clinical (animal testing) stage. However, we consider it to be a  promising therapy. The therapy will have to be further replicated in another lab, tested on a bigger number of animals in order to show robust effects and possible translation to the clinics.

KN combined gene therapy- Blackmore Lab – Pre-clinical stage (animal studies- USA)

Background info:

Funds from endParalysis enabled a pilot collaboration between Dr. Murray Blackmore at Marquette University and Dr. Steve Perlmutter at Washington University to test a new gene therapy treatment for chronic spinal cord injury. The animal study, funded by the endParalysis foundation in 2020- 2021, aimed to advance the promising new gene therapy approach for improving axon growth after CHRONIC spinal cord injury. It is based on a recent discovery from Dr Blackmore’s lab that a combination of two transcription factors, Klf6 and Nr5a2 (KN), stimulates robust and highly reliable growth from corticospinal tract (CST) axons. The goal here was to push in the direction of translation by determining whether KN is similarly effective in a more chronic and clinically relevant model of spinal contusion in the laboratory of Steve Perlmutter at the University of Washington. For more info about the project and its selection, read this blog post.

Latest update (May 2022):

The treatment has shown promise in animal testing when applied acutely to a mild injury, raising the question of whether it could be similarly effective in more severe and chronic injuries. With support from endParalysis the Blackmore and Perlmutter performed a series of experiments to establish viral designs and surgical techniques to deliver the treatment to rats in the chronic stage of spinal cord injury. Using these pilot data the two labs were able to secure additional funding from the Craig H. Nielsen foundation for expanded testing of this approach to enhancing repair and functional recovery after chronic spinal cord injury.

This figure illustrates successful and widespread gene delivery to injured neurons when administered in the chronic injury condition. This is an important prerequisite for translational development of this approach.

Patient enrolment/clinical trials/next translational steps:

This therapy is still at pre-clinical stage. Various studies need to be conducted before it is tested on human subjects with a spinal cord injury. 

 

Matricelf neural implants - ANIMAL STUDY (PRE-CLINICAL STAGE- ISRAEL) - HUMAN TRIALS PLANNED

Background info (May 2022):

A scientific paper was published in 2022 entitled “3D dynamic biomaterial-based mimicking the embryonic development of the spinal cord” . The tissue that was transplanted, a bio-scaffold, is a thermo-responsive hydrogel prepared from the patient’s omentum (matrix), combined with IPCS’s.   These Induced Pluripotent Stem Cells are adult stem-cells that are reprogrammed into pluripotent cells to subsequently offer a high differentiation potential.  In this case, these cells come from the patient himself and are reprogrammed into spinal cord motor neurons. The regenerative implants are able to bridge the injured spinal tissue.

Possible limits of the animal experiments: the results described in the paper are based on:

– mice with a hemi-section at T10 level, 6 weeks after the SCI. Why a semi-section rather than a complete contusion? A semi-section is considered, by some researcher, as sub-optimal , and hardly clinically-relevant injury model.

– scar-tissue resection: the solid scaffold / implant is inserted into the cavity after scar tissue resection. This is controversial within the scientific community as potentially useful nerve cells might be removed at the same time as the glial scar.

However, the first results are encouraging as paper highlights that MRI carried out after the treatment showed “a higher number of neurons with elevated expression of markers associated with sprouting of axons during development and regeneration. These results were translated into a significantly higher level of behavioral functional recovery, as judged by the sensorimotor functional analyses”.

 

Latest update (August 2023):

News (January 2023) from Matricelf website. “We are happy to announce that we met a very significant milestone within the company’s R&D plan.The development team was able to produce a complete human neural tissue implant. This process will be used to prepare the implants that will be tested in the coming weeks in experiments on animals and I hope that in the future they will be able to repair damaged spinal cord tissue in paralyzed patients

Previously, the company had also reported that they had successfully checked the feasibility of the therapy on a porcine model, more similar to the human model. More animal trials are planned before switching to human trials. 

Patient enrolment/ Experimental trial- PLANNED IN 2024 

The lab’s target is to test this therapy on human patients with a chronic SCI in 2024. Source: Matricelf’s website. Matricelf also highlights that the neural implants they plan to use will be patient-specific  and autologous (from the patient him/herself).

It is expected that the trial will include 5-10 people. The 2022 scientific publication clearly highlighted the importance of testing a therapy for SCI at the chronic stage, when spontaneous behavioural recovery has reached its plateau. It is therefore hoped that the human trials will involve people with a chronic spinal cord injury.

 

Mesenchymal stem cells from adipose tissue + EPO – Neurogel en Marche -TRIAL PLANNED- (China/France)

Background info:

In March 2019, twelve chronic spinal cord injuries (nine paraplegics and three quadriplegics) participated in an experimental trial at the International Treatment Center for spinal cord injury in Kunming, China. Six French patients and six Chinese patients received therapy to treat spinal cord injuries with an autologous cell growth matrix from adipose tissue called “fat enabled”and an associated medication with erythropoietin, more commonly known by the abbreviation EPO. Patients have followed up with intensive rehabilitation of 14 months. Even though this was not an “official” clinical trial and was not published on clinical trial registers, it is worth mentioning as it is arranged by a patient association, thus with non-profit purpose and with the honest aim of testing breakthrough therapies to patients in an accelerated pace, which is what so many patients are looking for. 

According to the Neurogel-en-Marche Association, “All patients had an ASIA-A score with a complete motor and sensitive paralysis with lesions sometimes over 6 cm. Patients continue to recover motor and sensory functions even today. They have not reached their progression threshold and continue to improve every day. The majority of patients had variable genital-sphincteric improvements” It has to be highlighted that the level of recovery is very variable and that some of it might also be due to the intensive 14-months of rehab they received. There is not yet any publication on the approach and the results of this human trial, but the French association states that a scientific publication is in preparation. More information can be found on their website: Accueil – NeurogelEnMarche

 

Latest update (August 2023):

Besides raising funds for another human trial using an autologous cell growth matrix from adipose tissue, either in France and/or in China, the foundation is also funding pre-clinical studies. The animal studies (on rats) are carried out by Prof. Dererchi from the University of Aix. Two studies are ongoing, one in acute settings (a few hours after injury) and another one in chronic settings (months later).

Patient enrolment/ Human experimental trial:

The association is currently working on a second experimental trial, maybe to take place in Europe and/or in China. More information can be found on their website: NeurogelEnMarche

Smart-cells - Intelligex - Dr M. Fehlings, Canada - Animal studies

Background info (August 2023):

Dr M. Fehlings created a biotech, Intelligex, in order to develop a combination therapy for spinal cord injury and bring it the clinic. The therapy is based on ‘Smart Cells” and address various issues brought by spinal cord injuries. Fehlings, in an interview in 2022 says: “Spinal cord regeneration is particularly challenging because at least three main cell types are damaged as a result of injury. For spinal cord regeneration to be successful we need the capability to replace:  1) Neurons that relay information via electro-chemical signalling, 2) oligodendrocytes that insulate the long processes extended by neurons known as axons, and 3) astrocytes that help maintain homeostasis in the nervous system.” 

Intelligex Smart-cells are pluripotent stem-cells. The treatment, tested on a cervical spinal cord injury model, should enable the axonal regeneration but also involves strategies to dissolve the glial scar and stimulate dormant neural connexions.

Latest update (August 2023):

Latest news available was Dr Fehlings interview, in 2021/ 2022, during which he described the vision and the strategies behind Intelligex.

Patient enrolment/ clinical trial:  

The target of the biotech is to make the smart-cells therapy ready and bring it to human patients. The treatment is still in very early stage and it will probably take quite some time until it is tried on human patients.  It is not known, at the stage, whether the trial will include chronic spinal cord injuries or not.

 

Other (STEM) CELLS clinical trials – Non exhaustive list/ summary (WORLDWIDE)

Background info:

Many clinical trials involving stem-cells or other cells transplantation are currently ongoing in an attempt to treat chronic spinal cord injury. What we show you below is a non-exhaustive summary only.

Latest update (August 2023)/ Patient enrolment/ clinical trial:

  • China – Guangzhou–  Umbilical Cord MSC transplantation – NCT03505034: This study is shown as completed. Unfortunately, no result was posted in clinical trials.gov

 

  • Vietnam-  Danang– Transplantation of autologous bone marrow-derived mononuclear cells by lumbar injection – Recruiting patients. More info: NCT02923817. sThis study is shown as “recruiting” but no update has been posted by the initiator of the trial for quite many years.  

 

  • China – Beijing–  Two trials seem to be ongoing involving the transplantation of NeuroRegen scaffold  with various types of stem cells.

 

– NeuroRegen with BMMCs or MSCs transplantation – more info: NCT02352077  . Enrolling by invitation

– NeuroRegen Scaffold with bone marrow mononuclear cells (BMMCs). More info on: NCT02688062, Enrolling by invitation

It has to be noted that results of a large human study/ clinical trial have recently been communicated regarding the transplantation of the NeuroRegen Scaffold in combination with either stem cells or  neurotrophic factors (to stimulate nerve growth). According to an article in Medical Express  (September 2020), “Among the 51 chronic complete patients, 16 patients achieved expansion of their sensation level and 30 patients experienced enhanced reflexive defecation sensation or increased skin sweating below the injury site. Nearly half of the patients with chronic cervical SCI developed enhanced finger activity, and some patients showed the expansion of motor evoked potential spinal cord segments.” In this page, we are focusing on the chronic stage of spinal cord injury, but please note that the article also includes (slightly more encouraging results) for the patients who received the transplant at an early stage after their spinal cord injury.

  • China: Biological: Umbilical Cord Mesenchymal Stem Cells- Intrathecal administration of UC-MSCs- More info: NCT02481440: Completed. Results of the trial have been published in clinical trials.gov, here

 

  • Brazil– autologous bone marrow mesenchymal stem cell transplantation – RECRUITING – more info:  NCT02574572 status:   unknown

 

  • Jordan– Bone-marrow stem-cells – leukapheresis-derived, purified, autologous CD34+and CD133- more info: NCT02687672 . Recruiting

ARCHIVE (OLDER RESEARCH OR TRIALS)

  • SEE SECTIONS BELOW TO CHECK INFORMATION ABOUT COMPLETED OR CANCELLED HUMAN TRIALS FOR WHICH RESULTS WAS PUBLISHED/ REPORTED.

Neuralstem Inc/ Seneca Biopharma. – Neural Stem Cells - USA - STOPPED?

Background info:

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 (NSI-566), on chronic spinal cord injury patients.  Four patients have been treated.  In October 2015, it was reported that the stem cells implantation had been safe and well tolerated.

 

Latest update (Sept 2021):

Ciacci was contacted for an update but we have not received any feedback so far. Actually, it appears that Neuralstem has long disappeared, as a company with an aim to cure or treat spinal cord injury and or find therapies for ALS. Firstly, it changed its name to Seneca Biopharma. This change of name was accompanied by a clear change of focus.  It then  became Palisade Bio after merging with another company, and is now focusing on gastro-intestinal therapies.   There is thus nothing left from the past endeavour to advance SCI and ALS research for a therapy or cure. It is another (sad) example, of how the market does not  work in our favour and how the aims of the patients are not always paired with the priorities of researchers and of investors.

 

Patient enrolment (clinical trials):

To date, the trial is still shown as recruiting patients on the clinicaltrial.gov website, but the latest input from Neuralstem on the subject dates back to June 2017, so it is unlikely that the trial is still active in anyway. The trial was being conducted at the university’s Sanford Stem Cell Clinical Center.  For more information on the Phase I Chronic SCI study, contact Ciacci’s Research Group at (619) 471-3698, nksidhu@ucsd.edu. More about the trial: on scitrials.org 

BioArctic – SC0806 (biodegradable device+ FGF1) – CANCELLED (Sweden/ Slovenia)

Background info:

SC0806 is a combination of a biodegradable medical device and a drug substance/ a growth factor (FGF1) and nerve implant designed to support nerve regeneration across the injured area in the spinal cord. The therapy is developed by BioArctic AB, a Swedish research-based biopharma company. BioArctic has received regulatory approval in Estonia for a clinical study in patients with Complete Spinal Cord Injury. BioArctic has received funding from the European Union’s Horizon 2020 Research and Innovation Program to carry out this project. The company also develops therapies for Alzheimer and Parkinson.

Latest update (Nov. 2021):

The company had  announced in February 2019 that the study with the product candidate SC0806 for complete spinal cord injury had progressed into Phase II. Safety and tolerability of SC0806 was assessed as acceptable. However, the results from the preclinical studies could not be replicated in man. No treatment effects were shown as measured by motor evoked potential (MEP) in any of the patients, i. e. the primary endpoint was not met. No convincing effects were seen on any of the secondary endpoints regarding motor function, other functions, or quality of life. Based on the results BioArctic decided to stop recruitment to the study. 

Unfortunately, the company has also decided not to further develop the complete spinal cord injury project after the final patient has completed the training program.

Patient enrolment/clinical trials:

The trial is cancelled.

 

Schwann Cells and combinations – Miami Project- COMPLETED (USA)

Background info:

The Miami Project launched their Schwann Cell clinical trial for chronic spinal cord injury patients in February 2015.  The transplanted cells are autologous (coming from oneself).

Latest update (Sept 2021):

The Schwann cell clinical trial completed its phase 1 (to check safety) and showed that the cells were safe.  The Miami Project is now carrying out further studies combining the Schwann cells transplantation with various other therapeutic strategies such as intensive physical rehabilitation.   Further studies are also in preparation and might involve the combination of Schwann cells with, respectively, growth factors, antibodies, and cell-support matrices.

Patient enrolment/ clinical trial:

This study has now been completed and does not recruit patients anymore. We are not aware of other open studies yet.

 

 

Theme 3

Re-training the spinal cord


Update: September 2023

Electrical / magnetic stimulation / TMS and BMI / BCI / AI

Introduction: E-stim (this term can refer to Electrical stimulation, neuromodulation, neuro-stimulation, epidural stimulation), Magnetic stimulation, TMS (Transcranial Magnetic Stimulation) and BMI /BCI (Brain Machine or Computer Interface) or AI (Artificial Intelligence):  all these technics use different protocols, involve various levels of invasiveness and produce various outcomes. They mostly have in common that they are using neurotechnologies and they aim to generate automated movement or improve autonomic functions through increased activity or through modulation of signals (e.g. bowel and bladder, blood pressure) and are therefore to be included in the quality of life/ care enhancement arena, rather than be considered as a therapy offering functional and sensory recovery or cure after spinal cord injury.  However, in case of e-stim, which explores  the automaticity of the spinal cord and then tries to tap into it, we might also see, in very few cases, a slight functional improvement (implying that a muscle previously totally paralysed and uncontrolled can be activated by the person even when the neuro-stimulator has been switched off  (but this “improvement” is mostly anecdotal, or concerns people who had an incomplete injury, or and not been the subject of many scientific publications yet). 

E-stim Industry/market update August 2023):  In September 2021, Onward Medical (previously known as GTX Medical and G-Therapeutics) announced their plan to join the Amsterdam and Brussels Stock Exchange. In April 2021, the company raised €26 million. Since its inception, it has raised approximately €70 m. Its shareholders also include the Christopher and Dana Reeve Foundation. Source: here. Onward Medical results from a merger between GTX Therapeutics and NRT (a start-up created earlier by Dr Reggie Edgerton), and now offers solutions for epidural stimulation through an implanted device as well as transcutaneous / external (non invasive) nerve stimulation. Other companies are also competing on a comparable market, for example Spinex.co, a new company funded by Dr Edgerton and focusing on non-invasive (trans-cutaneous) neuro-stimulation. Another newcomer in the field of neuro stimulation also appeared in the USA, i.e. Aneuvo. The latter is currently conducting clinical trials in various locations in the USA, using their TSS (Transcutaneous Spinal Stimulation) non-invasive device, ExaStim.

Apart from those business initiatives, a big number of trials or experiments are taking place around the world (more info below). Many of them are using a standard implanted Medtronic neurostimulator that has been implanted to stimulate patients spinal cord for decades in order to decrease neuropathic pain. 

Epidural Stimulation with an (implanted) (Medtronic or ARC/ Onward) stimulator- Many clinical trials ongoing/recruiting or planned

Background info: The patients receiving this kind of therapy undergo a surgery to transplant the electro-stimulation device (either a Medtronic electro-stimulator, the same one as used for fighting neuropathic pain, or a device recently developed by one of the new companies on the market) over a certain part of the spinal cord. The section of the spinal cord stimulated with electric current differs depending on what the aim of the therapy is, for example, motor function or bladder and bowel/ sexual function). Electro-stimulation of the cord is not a new system and was already used in some studies in 2000. However, the very first results of epidural stimulation with the Medtronic device were communicated in 2014. Since then, many large-scale clinical trials or tests have begun and more are planned in various parts of the world to check the isolated results published before. From the results known so far, E-stim should not be seen as a cure but rather as a way to improve the quality of life and/or enhance the outcome of physical rehabilitation. It does not repair the nerves but rather seems to stimulate the remaining connections and promote neuroplasticity. The interesting part of e-stim is that, in some limited cases, the (however limited) motor functions obtained through the stimulation when the e-stim device is on are actually seen to continue (for a limited time) after the device is switched off. 

Meanwhile, a number of companies have developed new systems for neuro-stimulation of the spinal cord and are testing them in various human trials.

Latest update/ Results published or reported so far (August 2023):

  • March 2019 – publication by Dr. Darrow (Minnesota). First results of the E-stand trial – for two women with a complete SCI): What is outstanding in this study is that the therapy includes e-stim but does not include any particular physio-therapy regimen. The results in the field of locomotion seem to be in line with results reported so far (i.e., the ability to move limbs on command when the device sends impulses). In both cases, significant quality of life improvement is reported through a level of autonomic function improvement. More interestingly, one of the two women reported that she can now experience orgasm when the device is on. More info: here

 

  • December 2018 (Dr. Krassioukov, Canada- single patient (with motor-complete but sensory-incomplete injury. Scope: bladder and bowel function). The 2018 publication mentions a positive effect of neuromodulation applied on the lumbosacral cord to modulate autonomic circuits involved in the lower urinary tract and bowel control after SCI. The study reports improvement of both urinary tract and bowel routine for this single patient, for example in terms of urodynamics (which could also result in a lower risk of a bladder infection) and a much shorter time needed for bowel routine. Although this improvement can be of value in terms of quality of life and care, rather than in terms of actual recovery, the study does not show an actual full recovery of the bowel and bladder function.
  • October 2018 (Dr. Courtine – EPLF Switzerland and GTX Medical (now ONWARD)- results for 3 incomplete SCI patients): the study shows that targeted electrical epidural stimulation coupled with an intensive regimen of locomotor training can help people with incomplete spinal cord injury improve their mobility. More details in our article here.
  • October 2018 (Mayo Clinic – EES results for 1 patient): Nature Medicine reported that a single patient with a spinal cord injury at the Mayo Clinic was also able to take steps and walk with trainer assistance thanks to electrical stimulation and intensive physical therapy. Beware: in this study, the e-stim has to remain on for the subject to take a step. The electric impulse given by the surgically-implanted stimulator is necessary to take the step. More details in our article here

  • October 2018 (Dr. Harkema – University of Louisville. Results of Epidural Electric Stimulation + intensive training for 4 patients): According to the Louisville publication, all four patients treated achieved independent standing and trunk stability (with the stimulator on). One of them can actually walk a short distance on her own, with the stimulator on and with the use of a walker. Beware: the patient with the best outcome had a motor-complete, but sensory-incomplete spinal cord injury (she had sensation below the level of her lesion, which is not often the case and does indicate that a number of nerve fibers are actually intact). Beware: in this study, the e-stim has to remain on for the subject to take a step. The electric impulse given by the surgically-implanted stimulator is necessary to take the step. All details in our article here
  • November 2017 (Dr. Harkema – scope: Autonomic functions, including bowel-bladder and sexual functions): A poster that was presented at the Neuroscience conference expanded a bit upon on the effect of e-stimulation on autonomic function, including bowel- bladder and sexual improvements. The poster remained rather vague about the range of improvement though and conclusion read: “Spinal cord epidural stimulation, along with activity-based training, may help provide an appropriate level of excitation to the spinal cord, targeting the neural circuitry involved in urogenital and bowel function”. More info: here.
  •  July 2015 (Dr. Harkema-Louisville- 4 patients- scope: motor control)– results for the first four patients were published (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 labelled as “really walking.”  Nevertheless, and this is the most interesting aspect of the study, these patients have all reported having 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.

 

Patient enrolment (update February 2024):

  • Switzerland: HemON study (Onward- Implanted stimulator:ARC-im): This trial, initiated by Onward, aims to see if epidural electrical stimulation can improve blood pressure and trunk control in those who suffer from blood pressure issues. The study is recruiting patients with a chronic (>=1 month) spinal cord injury at a C3-T6 injury level (More info: NCT05111093)
  • Minnesota – 100 patients: According to the E-stand website and as per scitrials.org, the trial is still recruiting patients with a chronic (>1 year) injury at C6-T10 level with Asia A (complete SCI) or Asia B rating (incomplete SCI).  Please check other details and important inclusion criteria here: NCT03026816
  • Kentucky (The Big Idea/Dr. Harkema):  This project (36 patients anticipated) for which Reeve foundation has been raising funds since 2014 is actually still recruiting patients.The characteristic of this trial is that it applies “task-specific” epidural stimulation. The investigators propose to understand the role of lumbosacral spinal cord epidural stimulation (scES) in recovery of autonomic nervous system function, voluntary movement, and standing in individuals with severe spinal cord injury (SCI).  Click here for more details.
  • UCLA (California, USA). This study  conducted by Dr Lu, is not recruiting anymore. It was focused on hand function recovery after implantation of an epidural stimulator in chronic cervical injury patients, combined with a drug treatment.  Click here for more details: NCT02313194  – Results don’t seem to be published yet

.

Transcutaneous e- Stimulation (through the skin) RECRUITING PATIENTS

Background information
Transcutaneous E-stimulation is more or less based on the same working principles as Epidural Stimulation.  However, transcutaneous stimulation does not require any surgery since the device works through the skin. The treatment is thus non-invasive, which is a big advantage vs epidural stimulation, and is therefore considered as risk-free* for the patients.

(*) Risks:  it has to be stressed that one patient, however, has reported a dramatic increase in his neuropathic pain after the treatment in 2018/2019. There is no other such case reported to-date and this can probably be considered as an exception, albeit a painful one.

As announced in our previous overview, the NRT company who was raising funds to develop and carry out a transcutaneous stimulation clinical trial in the USA has merged with another company, now known as ONWARD.  Meanwhile Dr. R. Edgerton founded another start-up company with just the same goal: SpineX. As per their new website, It now looks like the latter company has shifted focus and is not targeting electric stimulation for functional recovery after spinal cord injury. Instead, they offer treatments for urinary incontinence due to neurogenic bladder (NB, a condition known by spinal cord injury patients). Besides, they are also developing technology to treat the root cause of cerebral palsy (CP).

Meanwhile another company was set up to bring non-invasive spinal  electro stimulation on the market, by the name of Aneuvo and is also testing their Transcutaneous EES platform on patients with chronic paralysis following spinal cord injury.

 

Results known so far (update August 2023 – non-exhaustive) 

    • September 2022The ONWARD Study checking both safety and efficacy of their Transcutaneous Electro- Stimulation system, referred to as ARC-EX has been completed. The detailed results are under review, but the company states that: “Up-LIFT study achieves primary endpoint: Statistically significant and clinically meaningful improvement in upper extremity strength and function. ONWARD plans to submit for marketing approval in the U.S. and Europe with the goal to launch ARC-EX Therapy in the second half of 2023″.  Source: Business Wire Sept22

    • February 2020: Dr. Edgerton and Dr. Parag Gad show that “We found that TESCoN [the non-invasive transcutaneous e-stimulation therapy offered by the SpineX company, led to decreased detrusor overactivity, improved continence, and enhanced LUT [Lower Urinary Tract] sensation across the different pathologies underlying LUT dysfunction. This study serves as a pilot in preparation for a rigorous randomized placebo-controlled trial designed to demonstrate the effect of TESCoN on LUT function in neurogenic and non-neurogenic conditions”. To be noted that the trial was carried out on 14 patients with LUT dysfunction, 5 of whom with spinal cord injury (other patients had other pathologies, e.g. MS). We not talking about recovery of bladder function here but rather of an improvement of the symptoms. Read more in this 2020 publication.
    • May 2019 -On the Recovery Research Program website (page is now disabled), it read: “In a world-first, Professor Edgerton and his team have re-awakened the spinal cord and successfully restored feeling and function to more than 20 paralyzed people using non-invasive neurostimulation. Six of his patients have recovered hand movement, bladder and bowel control, sexual function and the ability to stand – unprecedented results in the history of medical science.” Once again it appears that the announcement was rather unprecise and very misleading. The only publication we found, is focusing on six patients only. It is noteworthy to add that these patients all had an INCOMPLETE spinal cord injury (Asia B or Asia C).  The publication (Sept. 2018) does document solid hand-grip improvement in all six patients and mentions some improvement in autonomous functions. 
    • July 2015: Dr. Reggie Edgerton’s group and NRT reported 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 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 occurred without any surgery.  This external stimulator technology is expected to be complementary to the implanted stimulators currently tried by other groups. 

     

    Patient enrolment (update August 2023)A few clinical studies using transcutaneous stimulation are underway or planned in various countries:

    • USA – ANEUVO – Aspire study: Ongoing- Eclipse study planned – 14 sites are currently testing the Aneuvo Transcutaneous Spinal Stimulation device (named Exa-Stim). The device is tested on people with a paralysis of upper limbs (tetraplegia/ Quadriplegia). 
      The company hopes to wrap up the Aspire study by spring 2014. Another study (The Eclipse Study) is expected to be launched soon to focus on people with a paralysis of their lower limbs (paraplegia). Source: Aneuvo website.

     

    • USA- SPINEX – SCONE CLINICAL TRIAL- Recruiting (USA and India). The purpose is to study the effectiveness and safety of SCONE™ neuromodulation therapy for individuals with neurogenic lower urinary tract dysfunction due to Stroke, Spinal Cord Injury, or Multiple Sclerosis. This trial is expected to be completed by April 2024.

    • Switzerland – Second panel of the Stimo study – Dr. Bloch- University of Zurich. Beware: patients with INCOMPLETE SCI only – Click for details: NCT03137108 –This trial is still active but not recruiting. Ten patients have participated in the trial, according to clinical trials.gov 

    Transcutaneous magnetic stimulation of the lower spine (through the skin) for improved bladder function (dr Lu, UCLA- USA)

     

    Background information
    In August 2018, neuroscientists were reported to have restored “significant bladder control” by five men with spinal cord injury. “We were excited to see a positive effect in all five patients after only four sessions of mild magnetic stimulation,” said Daniel Lu, the study’s principal investigator and an associate professor of neurosurgery at the David Geffen School of Medicine at UCLA. “The benefit persisted from two to four weeks, suggesting that the spinal cord’s neural circuitry retains a ‘memory’ of the treatment.”  While magnetic stimulation is quite similar to e-stim,  Lu’s team used magnetic stimulation because it’s non-invasive, painless and less costly than an electrical implant. Source: see this article

     

    Latest update/Results so far (September 2023):
    All five of the men regained the ability to urinate on their own during stimulation,” Lu said. “One patient — 13 years after his injury — was able to completely stop using a catheter and empty his bladder several times a day, up to four weeks after his last treatment.” For more detail see the August 2018 scientific publication The conclusion of that publication is that “neuromodulation of spinal micturition circuitry by TMSCS may be used to ameliorate bladder function”. The ability to urinate at will improved in each patient. Four of the men still had to use a catheter at least once each day — but that was still a significant drop from their average of more than six times a day before the treatment.

     

    Patient enrolment (Update September 2023):

    To our knowledge, many more patients have undergone the therapy and have shown progress. We are not aware of the current recruitment schedule but the clinicaltrials.gov website shows that the trial is still active and recruiting (USA). See  NCT02331979.  

      

    Transcranial Magnetic Stimulation (TMS) or Deep Cranial Stimulation - Recruiting patients

    Background information
    TMS uses electromagnetic induction to generate electrical currents in the brain and down the spinal cord.  Some recent studies by the University of Helsinki have shown that TMS could help patients acquire new voluntary movements and perform those movements for a while, even when the stimulation was turned off.

     

    Latest update (September 2023): 
    There are several studies underway (see below) in Cleveland, Boston and elsewhere in the world to evaluate TMS therapy spinal cord injury and other nervous system disorders.

     

    Patient enrolment (update September 2023)
    Various human trials are recruiting patients, for example:

    • University of Miami NINDS: NCT02446210 – Stil recruiting
    • University of Zurich (recruiting patients with an incomplete SCI, T10 and above. The study tests the effect of deep-brain stimulation on locomotion): NCT03053791 – recruiting (Switzerland). Expected completion date: December 2025
    • University of Sao Paulo (incomplete SCI only to check sensorimotor improvement after TMS). Be aware: inpatient rehab in Paraiba, Brazil) NCT02899637 – Trial status is unknown. The results have not been published but this study is probably completed or suspended.

     

    SYNCHRON "COMMAND" Clinical study – BMI – STENTRODE/ BIONIC SPINAL CORD – RECRUITING PATIENTS (USA)

    Background informationUniversity of Melbourne medical researchers, with financial sponsorship of, among others, DARPA (US Defense Department) have created a new minimally invasive brain-machine interface, aimed to enable people with spinal cord injuries to move limbs with the power of thought and through the use of an exoskeleton, or bionic limbs.  More info is available in this article.The brain-machine interface consists of a minimally invasive stent-based electrode (“stentrode”) that is implanted within a blood vessel next to the brain.  The “stentrode” records brain activity and converts the acquired signals into electrical commands, which in turn lead to movement of the limbs through a mobility assist device like an exoskeleton. More info about this project in this video. A new medical device and surgical technique have been developed, which allows implantation of the electrical sensors without open brain surgery. The device, called Stentrode™, is a small metallic mesh tube (stent), with electrode contacts (small metal disks) within the stent structure. It can be placed inside a blood vessel of the brain located in an area that controls movement (motor cortex). This does not involve open brain surgery.

    Latest update (September 2023):  A phase I clinical trial (SWITCH) was carried out to test the Stentrode™ device in participants with loss of motor function due to paralysis from spinal cord injury. It is now completed and showed the device and the implantation technique to be safe. There results were published here (January 2023 publication).  According to the publication, “At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI.[…] These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis”.

    Patient enrolment: A second clinical trial is currently recruiting patients (USA) to test the safety and feasibility of the device. The COMMAND trial is an early feasibility study (EFS) that will primarily assess safety while beginning to explore quantified efficacy measures of Synchron Switch™, a brain-computer interface device implanted through the blood vessels that allows people with no or limited mobility to operate technology such as mobile devices and computers using their thoughts. More info: NCT05035823.

     

    BMI for quadriplegic patients- Dr. A-Louis Benabid- Clinatec - France – RECRUITING PATIENTS

    Background information:  The Grenoble-Alpes University Medical Center (France) and regulatory authorities have granted Dr. Alim-Louis Benabid approval to begin the clinical research protocol “Brain-Computer Interface and Tetraplegia” at Clinatec.  The research aims to demonstrate the feasibility of a patient suffering from tetraplegia due to spinal cord injury to control an exoskeleton’s movements over several degrees via an implant that measures cerebral cortex activity. The study will focus on five patients and recruitment is underway.  Leti, a stakeholder in this research, has designed a permanent electrocorticography implant called Wimagine®, unlike any other in the world.  When placed on the surface of the cerebral cortex, it can transmit the brain’s signals reliably for years. Source: www. Minatec.org

     

    Latest update (September 2023): The first quadriplegic patient recruited within the trial was operated upon on June 21st, 2017.  An announcement by A.L Benabid, MD, Ph.D., during the latest WSSFN Congress in Berlin. It is not known to us whether more patients were already recruited and operated upon. The Clinatec website states: “Finalizing the BCI concept requires another €12.2 million for the system to be made reactive, easy to use and ready for distribution.” More info on the Clinatec website: here

     

    Patient enrolment (update September 2023)This trial is still recruiting patients, according to clinicaltrials.gov.  Be aware, candidates should be quadriplegic, aged 18-40 and fluent in French, among other criteria. The trial is expected to end by April 2029.  More info: NCT02550522

     

    Artificial Intelligence companies (AI) companies e.g.: NEURALINK

    Background information:  
    How could we report about BMI research, brain implants and various studies without mentioning Elon Musk’s Neuralink. The company invests into AI (Artificial Intelligence) and human augmentation, It envisions, among other goals, to help people suffering from neurological conditions/ diseases. The idea is that patients with a neurological shortcoming will be able to compensate that by using a direct communication between their brain and a computer or a machine. An electrode is implanted in your skull and transmits the order directly to the computer or the machine/ device. This is how we could see images of a chimp paying a computer game without using his hands but simply using his thought. There is also the possibility for people who cannot use their hands to control their smartphone directly with their mind.

    Is this part of “Cure Spinal Cord Injury latest therapies, research, treatments?”  Well, this is definitely argue-able. EndParalysis foundation’s opinion about those discoveries is that, however fascinating they might be, they are to be seen as compensatory measures rather than future therapies for repairing and reversing paralysis. Read our article about this: Here.

     

    Latest update (February 2024): 

    Elon Musk announced on X that a first patient had just received the Neuralink brain implant that should enable him or her to control a number of appliances with his/her mind. More here

    Neuralink shared, via a Tweet, in May 2023, that they had received the FDA’s approval to launch their first-in-human clinical study. The latest version of the “Link” has already been tested on monkeys, pigs. It was previously stated that the BMI device would be tested on a patient with a cervical spinal cord injury.

     

    Patient enrolment (update February 2024):
    The first patient has been enrolled and operated upon. But the Neuralink’s clinical trial does not seem to be included in clinical trials.gov.  

     

    Brain-Machine Interface (BMI)- Walk Again Project (WAP) - Dr. Miguel Nicolelis - Brazil

    Background informationWe regularly hear about paralyzed people being able to move a limb “just” by using their thought, i.e. by making use of a Brain-Machine Interface.  This was also the principle behind the experiment led and published in August 2016 by Dr. Miguel Nicolelis in Brazil (see Nature publication here). Eight paralyzed patients (out of which seven people had a complete spinal cord injury) were reported to recover partial neurologic function, both sensory and motor after a full year of training using a non-invasive BMI skullcap, along with a virtual reality training method.  As per the paper:  “Following 12 months of training with this paradigm, all eight patients experienced neurological improvements in somatic sensation (pain localization, fine/crude touch, and proprioceptive sensing) in multiple dermatomes.  Patients also regained voluntary motor control in key muscles below the SCI level […].  As a result, 50% of these patients were upgraded to an incomplete paraplegia classification. […] – As per the paper, the hypothesis is the neurological recovery results from both cortical and spinal cord plasticity triggered by long-term BMI usage. Next, to awakening dormant spinal cord nerve networks, the virtual training, which also includes bio-feedback, could also have helped the patient’s brain recover a previously erased representation of his lower limbs.

     

    Latest Update (September 2023)See the latest update about this project here.  According to this article: “Two patients with paraplegia regained the ability to walk with minimal assistance, through the employment of a fully non-invasive brain-machine interface that does not require the use of any invasive spinal cord surgical procedure”. The website dedicated to the Walk Again project is not online anymore. It is therefore unclear whether this project and approach will be followed by further research or human trials. Also, it has to be noted that the study however exciting from a scientific viewpoint, is yet limited to a laboratory experiment on a small number of patients.  Further investigation will be necessary to distinguish the impact of the heavy training from the pure BMI effects on the patient’s partial recovery before it can be applied in “real” life. 

    Find clinical trials for YOUR spinal cord injury?

    There is currently no cure for spinal cord injury and all therapies mentioned on this page are actually experimental, i.e. without any guarantee for results and including a certain level of risk taking.

    However, the so-called Unproven / Commercial Therapies, often referred to as “medical tourism or stem-cell tourism” are even more experimental as they do not follow regulatory protocols nor do they provide any sort of transparency or scientific follow-up.  These therapies are referred to as “commercial” because patients have to pay for them, unlike a listed clinical trial for which participation is free.

     

    How to find clinical trials suitable for you?

    Clinical trials are experimental and therefore do not guarantee any result. However, they do contribute to scientific progress and might bring you personal improvement.

    If you want to find and possibly enrol in clinical trials now or in the future, or simply keep track of what is going on, we recommend visiting and subscribing to www.scitrials.org. 

    Clinical trials are:

    • scientifically driven
    • transparent in terms of protocol and results
    • free (you should NOT be charged for an experimental therapy)
    • approved by regulatory organizations and listed in clinicaltrials.gov  
    How to avoid "unproven" therapies?

    We don’t want to ignore these therapies since a lot of patients do make use of them, often at a high cost, but we do want to warn readers about the absence of proven functional results, the cost, the lack of transparency and the possible risks attached to these experimental treatments.They are heavily marketed and therefore easy to find on internet.


    Unproven/ Unregulated therapies are:

    • not always scientifically driven and possibly risky
    • not transparent in terms of protocol and results (no publication)
    • costly (you will be charged for the cost, without any guarantee) 
    • not approved by regulatory organizations and listed in clinicaltrials.gov 

     For further information on the theme “Unproven / unregulated/ for profit experimental therapies versus clinical trials”, we invite you to view the presentation in this blog post.

    Latest research articles/ blog/ news

    These are only a few blog articles and archives written about key developments about spinal cord injury research. To stay informed about key research development in the field of curative chronic SCI research, make sure to check our very latest Research overview above.  To know more about the projects that we fund and their outcome, please read our latest annual report and consult “Our research funding” page. Thank you! 

     

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