Dwarslaesie onderzoek

Onderzoek overzicht

Vind klinisch trial

Onderzoeksblog

Vooruitgang geboekt bij de genezing van dwarslaesie

Er is aanzienlijke vooruitgang geboekt bij onderzoek in de labs. Verschillende veelbelovende onderzoekslijnen worden hieronder belicht.

Worden behandelingen op mensen getest?

Er vinden wereldwijd steeds meer klinische proeven plaats. Ons overzicht bevat informatie over lopende of geplande studies bij mensen.

Wanneer zullen therapieën beschikbaar zijn voor iedereen?

De meeste behandelingen zijn momenteel nog experimenteel, maar een positief teken is dat er steeds meer biotechs/commerciële bedrijven worden opgericht en investeren in het naar de kliniek brengen van veelbelovende dwarslaesie-therapieën.

 Dwarslaesie onderzoek, therapieën & behandelingen
Laatste update (juni 2022)

 Openbaarmaking


Dit overzicht is uitsluitend gericht op een aantal belangrijke onderzoeksprojecten of therapieën naar herstel / genezing na chronisch ruggenmergletsel. Het is niet bedoeld om uitputtend te zijn. Onderzoek gericht op acute letsels is niet opgenomen. Dit overzicht is ook op geen enkele wijze een aanbeveling voor of een onderschrijving van een van deze projecten of klinische studies.ials.

Thema 1: Regeneratie (Stamcellen & combinatie voor neuraal herstel)

Thema 2: Littekenvermindering, groeifactoren & anti-remmers

Thema 3: Elektrische stimulatie & neuro-technologieën

Thema 1

Laatste update: 14 juni 2022

Herstel-/neuro-regeneratieve therapieën: (stam)cellen, biomaterialen / scaffolds / hydrogels, groeifactoren en/of combinaties voor functioneel en sensorisch herstel na een chronische dwarslaesie

Introductie:

Ruggenmergletsel leidt tot aanzienlijk weefselverlies en een aantal strategieën is gericht op vervanging en herstel van de cellulaire architectuur in de hoop herstel te bevorderen. Dit omvat bijvoorbeeld (stam)cel-transplantatie-therapieën, of transplantatie van 3D-biotechnisch weefsel ter vervanging/ herstel van beschadigd weefsel/ zenuwen. Deze strategieën kunnen verder worden uitgebreid door ze te combineren met groeifactoren of -moleculen om de neurale hergroei te bevorderen en met biomateriaalsteigers om de zenuwhernieuwde groei te begeleiden. Het kan ook gaan om andere strategieën ter bevordering van neuro-regeneratie en neuroplasticiteit (d.w.z. de hermodellering van signalen van de hersenen en de zenuwen in het ruggenmerg). De onderstaande lijst is uitsluitend gericht op behandelingen die mogelijk van toepassing zijn op chronische dwarslaesie, overeenkomstig de focus van onze stichting, en omvat slechts enkele van de talrijke preklinische onderzoeksprojecten wereldwijd, alsmede de meeste belangrijke geplande of lopende proeven bij mensen die gericht zijn op een niveau van functioneel herstel. Het is niet uitputtend en vormt in geen geval een aanbeveling voor een bepaalde experimentele therapie.

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 (May 2022):

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 May 2022):

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 (Sept 2021):

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 Sept. 2021 

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: https://walk-again-project.org/#/en or on NCT03933072

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 planned 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.

 

Latest update (January 2022):

The clinical trial was expected to start in 2021 but had to be delayed because priority was given to COVID patients. This trial is interesting because it will be the first time that IPS cells are used to treat spinal cord injury (they have already been used to treat other conditions). In a Sept. 2021 scientific publication, we learn that the trial will focus on sub-acute SCI patients, which is within two to four weeks of sustaining a spinal cord injury. Hopefully, chronic SCI patients can also be included at a later stage but there is no mention of that. This study is a phase I clinical trial, thus is mainly aimed at checking whether the therapy is safe. The article states: “The primary focus of this clinical study is safety, and the number of transplanted cells may be too low to confirm efficacy. After confirming safety, a dose-escalation study is planned.” 

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”.

Patient enrolment/Clinical trials:

This trial is not published yet in clinicaltrials.gov. The abovementioned publication states “We plan to start recruiting a patient as soon as the COVID-19 epidemic subsides”. In total, four patients are expected to be recruited.

 

 

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 (May 2022): 

Clinical trial in the USA in preparation. According to communication in May 2021, the team had obtained the authorization from the FDA to carry out the trial. However because of COVID-19, the trial sponsor backed out and they are now working on the new IND and raising money for the trial. In a recent presentation (Sept. 2021), Dr. Young has indicated that the trial will 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 has recently been 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. Hope to start the trial later this year., thus still needs approval from the FDA (and funding from sponsors).

 

Patients enrolment (update May. 2022):

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, but in Taiwan and is currently recruiting patients in Taiwan. 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 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), June 2018 publication (for both complete and 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).

Latest update (Sept. 2021): 

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 trials. Some information about the trials is available though, on the following page in Spanish.

 

Patients enrolment (Clinical trials): 

This trial is not yet published on clinicaltrials.gov and is not yet recruiting. Beware: this trial would ONLY recruit patients from 18 years to 65 years with an INCOMPLETE low SCI (T or L level). It is possible that the trial recruits only candidates from Spain. If you are interested, we advise you to check all information on this page in Spanish   (which also includes an application form for the NC1 therapy clinical trial)

 

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 (May 2021):

In March 2022, Neuroplast announced that they just enrolled their first patient in a Phase II clinical trial to evaluate the efficacy of their stem-cells treatment on acute Traumatic Spinal Cord Injury. In November 2020, Neuroplast had already reported that their first patient with chronic spinal cord injury had been treated with Neuro-Cells in Toledo, Spain, as phase I of the trial, showing the safety of the therapy.  The current phase II/III is expected to enrol further patients in Spain and Denmark.

Patient enrolment/clinical trials:

The new trial, involving people with a traumatic acute / sub-acute spinal cord injury (6-8 weeks after lesion) is now recruiting in Spain. It is not yet recruiting in Denmark. 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”, which is very interesting.

"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 (May 2022):

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 authorised the therapy to be tested on humans). 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. 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 would have to be discussed with neuro-surgeons.

Besides, Stupp informs that he is willing 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.

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 (May 2022):

Next to the rodent trial, the company 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.

 

Latest update (May 2021):

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

 

Patient enrolment/ Experimental trial:

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

 

 

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 (Sept 2021)/ Patient enrolment/ clinical trial:

  • China – Guangzhou–  Umbilical Cord MSC transplantation – NCT03505034: Recruiting patients

 

  • Vietnam-  Danang– Transplantation of autologous bone marrow-derived mononuclear cells by lumbar injection – Recruiting patients. More info: NCT02923817 status unknown

 

  • 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: NCT02688062Enrolling 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

 

  • 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: NCT02687672Recruiting

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.

 

 

Thema 2

Laatste update: 14 juni 2022

Vermindering van littekens en groeiremmers & combinaties voor herstel. 

Introductie:

Een van de grootste problemen die herstel na een chronische ruggenmergletsel in de weg staan, is het litteken dat enkele dagen of weken na het letsel ontstaat en dat verhindert dat axonen uit het letselgebied weg kunnen groeien. Een van de belangrijkste strategieën om het litteken te verminderen is het gebruik van het enzym Chondroitinase. Verschillende peptiden worden ook voor dat doel getest.
Daarnaast worden in dit hoofdstuk ook enkele van de verschillende therapeutische strategieën beschreven die worden gebruikt om groeiremmers (vaak NoGo genoemd) na de ruggenmergletsel te neutraliseren en/of de zenuwgroei te bevorderen.

ReNetX Bio – NOGO TRAP - NOT RECRUITING PATIENTS ANYMORE (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 (Nov. 2021):

In November 2021, ReNetX Bio announced that they have completed enrolment of RESET Study of AXER-204 for Chronic Spinal Cord Injury. More info here. first results are expected to be reported in Q2/Q3 2022

Patient enrolment/clinical trials:

This trial is NOT recruiting patient anymore. More info on this trial can be found here: https://scitrials.org/trial/NCT03989440

 

Drug ES 135 (growth factor) – Human trial Phase 3- CURRENTLY RECRUITING PATIENTS (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 (Jan. 2022):

The human trial started in 2016 and is expected to last until 2024 according to clinicaltrial.gov.

Patient enrolment/clinical trials:

160 patients with complete or incomplete SCI are expected to be recruited in Taiwan. However, the patient recruitment criteria are not precise and do not indicate if the therapy is applied at the acute or chronic stage. 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)

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 endParalysis started to support the translation of this potential therapy from the lab to the clinics (i.e. to humans) in 2018. The non-invasive character of the CRP (it can be applied by subcutaneous injection) is of great interest. CRP treatment, if proven effective, will, 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. Indeed, the latter treatment requires a specific and elaborate delivery method to safeguard its effectiveness as well as safety for the patient.

 

Latest update (Oct. 2021):

– 2018-2019 rodent study, 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 the endParalysis foundation, 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 Dr. Jerry Silver’s lab to have a robust effect at the ACUTE stage).

    (*) Abstract from the Lee lab’s report:”The study seems to show that CRP enhanced connectivity established across injury site and nerve sprouting below the injured site after treatment, as well as an improved function for both locomotion and bladder (the CRP-treated groups show less hyperactivity, better void efficiency, and lower voiding pressures)”

    (**) Abstract from the Lee Lab’s report: “While there was a trend showing CRP+ISP works slightly better in improving BBB scores (BBB is a test of stepping function) than CRP alone, there was, overall, no significant difference between the CRP+ISP and CRP groups”.

     

    – 2020-2021 dosing (rodent) study:  the CRP dosing study (funds pre-allocated by endParalysis at the end of 2019) is  mainly testing dose responses of CRP to see if a higher dose can lead to an additional functional improvement, after chronic spinal cord injury. This study suffered some delay due to the COVID-19 lockdown measures. However, the preliminary progress report relates very encouraging results. We expect the final report to be available by the end of 2021 and will share the conclusion on our website.

    Patient enrolment/clinical trials/ next translational steps:

    – We hope to receive the final results of the 2020 CRP dosing animal study funded by endParalysis by the end of February 2022

    – Meanwhile, Dr. Yu-Shang Lee has been working with Dr. Brian Kwon to investigate the efficacy of CRP in a large animal model using mini-pigs T10 subacute stage injury model to test both locomotion and bladder function. The study progress has also been delayed by COVID-19 and results are expected in 2022.

    – Next step for the CRP therapy will be conducting Pharmacokinetics and Safety/toxicity tests of CRP. Those are necessary for any therapy to go to spinal cord injury clinical trials.

     

    ISP ( Intracellular Sigma Peptide) / NVG-291– Dr. Jerry Silver/ Nervgen biotech – CLINICAL TRIAL PLANNED ( 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 develops into a barrier to the regrowth of the cut axons. Dr Jerry Silver and his team at Case Western Reserve University have developed a molecule, known as intracellular sigma peptide (ISP) that negates this signal, allowing the regenerating axons to ignore and bypass CSPGs (the active part of the scar tissue). When ISP was administered noninvasively via injections under the skin, it has been 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 (Jan 2022):

    In January 2022, Nervgen announced its intention 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

    Noticeably, the clinical trial is expected to include not only patients at acute and sub-acute stage but also at chronic stage of the injury. This is surprising for animal studies have not, so far, proven ISP/ NVG-291 to result into any significant functional improvement in the case of chronic injuries, unless delivered in combination with other therapies. 

    Patient enrolment/clinical trials:

    The clinical trial has been announced but is not yet included in clinicaltrials.gov. The trial is expected to be conducted in a single site, in partnership with the Shirley Ryan AbilityLab in Chicago. The trial is scheduled to start in the second half of 2022.

    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 (Nov. 2021):

    • UK: alternative delivery method for Ch’ase. More info: here
    • CANADA: alternative  delivery method for Ch’ase.
    • USA: study of non-human primates.
    • USA: Rose Bengal Study by Dr. A. Parr (University of Minnesota). See January 2018 publication 

     

     

     

    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 (Nov. 2021):

    PNNi dosing study (including chronic SCI) by the Kwok Lab: this study was co-funded by the endParalysis foundation at the end of  2020 together with two other foundations: We thank the Marina Romoli Onlus (Italy) and  Gusu2cure (USA) for accepting to fund this project with us.  The animal study is ongoing. It is aimed to check if the PNNi molecule (an oral drug) works as well in chronic settings as in acute settings, and whether a higher dose is needed for chronic spinal cord injury. Also it will be scientifically checked what lowest possible quantity enables to keep the therapeutic effects intact while avoiding unfavourable side-effects. The first report regarding this study is positive, but the final report will only be received in 2022.

    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 need to be conducted before it is tested on human subjects with a spinal cord injury. 

     

    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 and 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. 

     

    Microcure and University Pre-clinical stage (animal studies- USA)

    Background info:

     

    Latest update (Nov. 2021):

    Patient enrolment/clinical trials/next translational steps:

     

    Thema 3
    Update: mei 2022

    Elektrische / magnetische stimulatie / TMS en BMI / BCI / AI

     Introductie: E-stimulatie (deze term kan verwijzen naar Elektrische stimulatie, neuromodulatie, neurostimulatie, epidurale stimulatie), Magnetische stimulatie, TMS (Transcraniële Magnetische Stimulatie) en BMI /BCI (Brain Machine of Computer Interface) of AI (Artificiële Intelligentie): al deze technieken maken gebruik van verschillende protocollen, zijn niet allemaal even ingrijpend en leveren verschillende resultaten op. Ze hebben meestal gemeen dat ze gebruik maken van neurotechnologieën en gericht zijn op het genereren van geautomatiseerde bewegingen of het verbeteren van autonome functies door middel van verhoogde activiteit of door modulatie van signalen (bv. darm en blaas, bloeddruk) en moeten daarom worden opgenomen in de arena van de kwaliteit van leven/zorgverbetering, eerder dan te worden beschouwd als een therapie die functioneel en sensorisch herstel of genezing na ruggenmergletsel biedt.  In het geval van e-stim, waarbij de automatismen van het ruggenmerg worden onderzocht en vervolgens getracht wordt deze aan te boren, zouden we echter ook, in zeer zeldzame gevallen, een lichte functionele verbetering kunnen zien (wat impliceert dat een spier die voorheen volledig verlamd en ongecontroleerd was, door de persoon kan worden geactiveerd, zelfs wanneer de neurostimulator is uitgeschakeld (maar deze “verbetering” is meestal anekdotisch, of betreft mensen die een onvolledige verwonding hadden, of en is nog niet het onderwerp geweest van veel wetenschappelijke publicaties). 

    E-stim Industry/markt update (oktober 2021):  In september 2021 kondigde Onward Medical (voorheen bekend als GTX Medical en G-Therapeutics) hun plan aan om toe te treden tot de Amsterdamse en Brusselse beurs. In april 2021 haalde het bedrijf €26 miljoen op. Sinds de oprichting heeft het ongeveer 70 miljoen euro opgehaald. Onder de aandeelhouders bevindt zich ook de Christopher and Dana Reeve Foundation. Bron: hier.. Onward Medical is het resultaat van een fusie tussen GTX Therapeutics en NRT (een start-up die eerder werd opgericht door Dr. Reggie Edgerton), en biedt nu oplossingen voor epidurale stimulatie via een geïmplanteerd apparaat, alsook transcutane/externe (niet-invasieve) zenuwstimulatie. Andere bedrijven concurreren ook op een vergelijkbare markt, bijvoorbeeld Spinex.co, een nieuw bedrijf dat wordt gefinancierd door Dr. Edgerton en zich richt op niet-invasieve (transcutane) neurostimulatie. Afgezien van deze bedrijfsinitiatieven vindt over de hele wereld een groot aantal proeven of experimenten plaats (meer info hieronder). Bij vele daarvan wordt gebruik gemaakt van een standaard geïmplanteerde neurostimulator van Medtronic die al tientallen jaren wordt geïmplanteerd om het ruggenmerg van patiënten te stimuleren met het oog op de vermindering van neuropathische pijn.

    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 (until now a Medtronic electro-stimulator, the same one as used for fighting neuropathic pain) 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.

     

    Latest update/ Results published or reported so far (May 2022):

    February 2022 – publication by Dr Courtines (Switserland)/ ONWARD:  The 2022 paper published in Nature highlights the results of EES with the new ONWARD Lead. It was tested in three individuals with complete sensorimotor paralysis as part of the STIMO clinical trial (currently not recruiting). According to the paper “Within a single day, activity-specific stimulation programs enabled these three individuals to stand, walk, cycle, swim and control trunk movements”. It is noteworthy that the capability to move stops as soon as the stimulator is switched off and that the paper only sees a very limited level of regeneration. The results shown are nevertheless impressive and it looks like the type of leads and the preciseness with which it is used, thanks to very dedicated programs, on various part of the spinal cord and with various adjusted settings, enabled very quick usability and diversity of use. The described use is still more likely to be therapeutic. It is not a biological functional return. If it could be tuned in such a way and most importantly be made available to more people (which remains a huge question mark, as individuals involved in such a clinical trial are always subject to a long list selection criteria and seem to be the exceptions rather than the majority as far as functional return potential is concerned. Whether it can really lead than an actual community use or will remain a rehabilitation/ or a therapeutic device, also remains to be seen.PS: this study did unfortunately not test the impact of the e-stim on bowels, bladder and sexual function, which would have been very welcome by patients.

     

    •  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.

       

    • 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

       

    • 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 May 2022):

    • Minnesota – 100 patients: According to the E-stand website, 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. Click here for more details.

       

    • Europe – Switzerland – The Netherlands– STIMO 2 study: GTX Medical (now ONWARD) and the Sint Maarten Kliniek in Nijmegen (the Netherlands) announced that a study was expected to start by end 2019 and would recruit people who have just acquired an incomplete spinal cord injury at T10 or higher. Be aware: ACUTE (very recent) and INCOMPLETE injuries only. According to ClinicalTrials.gov, this study is “on hold before first recruitment” (status September 2021).  More info: NCT04196114.  It is not clear whether the STIMO 2 study will take place and whether it will include the new implantable platform ARCim or an older generation device. ARC im is ONWARD’s  implantable platform, which consists of an implantable pulse generator and lead that is placed near the spinal cord. ARCim is controlled by wearable components and a smartwatch.

      Active studies, not recruiting anymore:

    • 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. Professor Edgerton now also spearheads a program in Australia along with Professor Bryce Vissel. It is not clear yet if that program will be focusing on solely transcutaneous e-stim or a combination of various kind of e-stim.

     

    Results known so far (update MAY 2022 – non-exhaustive):

    • 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 May 2022)A few clinical studies using transcutaneous stimulation are underway or planned in various countries:

    • Switzerland – Second panel of the Stimo study – Dr. Bloch- University of Zurich. Beware: patients with INCOMPLETE SCI only – Click for details: NCT03137108 – active but not recruiting

    • USA – Shepherd Center NIH: Only recruits patients with an Incomplete SCI level T12 and above and aims at checking dose-response (check the impact of amount/intensity/frequency of transcutaneous e-stim on the potential improvement for the patients.  Click for details: NCT04697472
    • USA, CANADA, EUROPE (including the Netherlands and UK) – UP-LIFT trial: The Up-LIFT Study is a study designed to evaluate the safety and effectiveness of non-invasive electrical spinal cord stimulation (ARCEX Therapy, offered by the ONWARD company) administered non invasively (through the skin) to treat upper extremity functional deficits in people with chronic INCOMPLETE tetraplegia. Recruiting patients with non-progressive spinal cord injury from C2-C8 inclusive. They plan to enrol 65 subjects in total. The study is currently recruiting. More information on NCT04697472

     

    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 (Update May 24, 2019):
    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 May 2022):
    To our knowledge, many more patients have undergone the therapy and have shown progress. This trial is still recruiting patients (USA). We are not aware of the current recruitment schedule but the clinicaltrials.gov website shows a still active trial in that field. See  NCT02331979recruiting

     

     

    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 (May 2022): 
    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
    Various human trials are recruiting patients, for example:

    • University of Miami NINDS:NCT02446210 – 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
    • 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

     

    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 (May 2022)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. 

    Melbourne, Australia “SWITCH” Clinical study – BMI – STENTRODE/ BIONIC SPINAL CORD – RECRUITING PATIENTS

    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.

    Latest update (May 2022):  According to the website: “An early feasibility study of the safety  (phase I trial) of the Stentrode™ device in participants with loss of motor function due to paralysis from spinal cord injury, motor neuron disease, stroke, muscular dystrophy or loss of limbs. The purpose of this research is to evaluate the safety of the Stentrode™ device in humans. This is an experimental device. 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.This research will be the first of its kind to be performed in humans and may help us find safer, more effective ways to introduce/implant electrical sensors in patients’ brains”.

    Patient enrolment: The SWITCH study is active but no longer recruits patients. Five patients, including a few SCI patients, were expected to be recruited. More info: NCT03834857.

     

    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 (May 2022): 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. More info on the Clinatec website: here

     

    Patient enrolmentThis 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.  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 (May 2022):
    The latest version of the “Link” has already been tested on monkeys, pigs. It is expected to be tested on a patient with a cervical spinal cord injury in 2022

     

    Patient enrolment:
    unknown.

     

    Klinische trials vinden voor UW dwarslaesie?

    Er is momenteel geen genezing voor dwarslaesie en alle therapieën die op deze pagina worden genoemd zijn feitelijk experimenteel, d.w.z. zonder enige garantie voor resultaten en inclusief een bepaald niveau van risico nemen.
    De zogenaamde onbewezen / commerciële therapieën, vaak aangeduid als “medisch toerisme of stamceltoerisme” zijn echter nog experimenteler, aangezien zij geen regelgevende protocollen volgen en geen enkele vorm van transparantie of wetenschappelijke follow-up bieden.  Deze therapieën worden “commercieel” genoemd omdat patiënten ervoor moeten betalen, in tegenstelling tot een geregistreerde klinische proef waaraan gratis kan worden deelgenomen.

     

    Hoe vindt u klinische trials die geschikt zijn voor u?

    Klinische proeven zijn experimenteel en garanderen dus geen enkel resultaat. Ze dragen echter wel bij aan de wetenschappelijke vooruitgang en kunnen u persoonlijk vooruit helpen.
    Als u nu of in de toekomst klinische trials wilt vinden en u er eventueel voor wilt inschrijven, of als u gewoon op de hoogte wilt blijven van wat er gaande is, raden wij u aan www.scitrials.org te bezoeken en u erop te abonneren. 

    Clinical trials are:

    • wetenschappelijk gedreven
    • transparant in termen van protocol en resultaten 
    • gratis (u mag GEEN kosten worden aangerekend voor een experimentele therapie)
    • goedgekeurd door regelgevende organisaties en opgenomen in clinicaltrials.gov
    Hoe "onbewezen" therapieën te vermijden?

    Wij willen deze therapieën niet negeren omdat veel patiënten er gebruik van maken, vaak tegen hoge kosten, maar wij willen de lezers wel waarschuwen voor het ontbreken van bewezen functionele resultaten, de kosten, het gebrek aan transparantie en de mogelijke risico’s die aan deze experimentele behandelingen verbonden zijn.Zij worden op grote schaal op de markt gebracht en zijn daarom gemakkelijk te vinden op internet.

    Onbewezen/ ongereguleerde therapieën zijn::

    • niet altijd wetenschappelijk onderbouwd en mogelijk risicovol 
    • niet transparant wat betreft protocol en resultaten (geen publicatie)
    • kostbaar (de kosten worden u in rekening gebracht, zonder enige garantie) 
    • niet goedgekeurd door regelgevende organisaties en opgenomen in clinicaltrials.gov 

     Voor nadere informatie over het thema “Onbewezen / ongereguleerde / uit winstbejag experimentele therapieën versus klinische proeven” nodigen wij u uit de presentatie te bekijken in deze blog post en presentatie over onbewezen / experimentele behandelingen voor dwarslaesie.

    Laatste onderzoeksartikelen/ blog/nieuws

    Dit zijn slechts een paar blog artikelen en archieven geschreven over belangrijke ontwikkelingen op het gebied van ruggenmergletsel onderzoek. Om op de hoogte te blijven van belangrijke onderzoeksontwikkelingen op het gebied van curatief chronisch dwarslaesie-onderzoek, moet u zeker ons allerlaatste Onderzoeksoverzicht hierboven bekijken.  Om meer te weten te komen over de projecten die wij financieren en hun resultaten, lees dan ons laatste jaarverslag en raadpleeg “Onze onderzoeksfinanciering” pagina. Hartelijk dank! 

     

    Artikel dwarslaesie magazine
    Artikel dwarslaesie magazine

      Dwarslaesie Organisatie Nederland (DON) en endParalysis over dwarslaesie-onderzoek Geschreven door Annet  Verlouw voor Dwarslaesie Magazine Juni 2018.  Dwarslaesie Organisatie Nederland (DON) en endParalysis over dwarslaesie-onderzoek Revalidatiearts Janneke...

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