Spinal cord injuries: how could stem cells help?
The spinal cord transmits information between the brain and the rest of the body. Injury to the spinal cord, which currently affects some 333,000 Europeans, can cause paralysis, and there is currently no effective treatment. Could stem cells help?
The spinal cord is a collection of millions of nerve cells (neurons) inside our spine that sends signals to and from the brain. Damage to this important and delicate tissue is often permanent and can result in paralysis.
There are presently no effective treatments for restoring spinal cord function.
However, several current clinical studies are testing the safety and effectiveness of stem cells as treatments. These treatments hope to at least partially restore function to the spinal cord. Several studies have shown promising results, but definitive outcomes are still unknown.
Inflammation and toxins released by damaged cells at the site of a spinal injury often cause further harm to surrounding cells. Researchers are developing treatments that reduce inflammation and soak up toxins and free radicals to minimise additional damage.
Spinal cord injuries often damage neurons and the supporting cells that wrap & insulate neurons. Damaging the supporting cells can cause otherwise functional neurons to die. Researchers are studying how stem cells might be used to replace neurons and their supporting cells to greatly improve a patient’s chances for recovering function.
Most stem cell treatments presently in clinical trials rely on transplanted stem cells to automatically repair damaged areas of the spinal cord. It’s not known how reliable and reproducible this treatment will be for different patients and types of injuries.
Stem cell treatments for spinal cords are thought to work best if offered in the short time-frame after an injury. Scarring at the site of injury can hinder the effectiveness of a treatment, so this also needs to be addressed.
It isn’t yet clear how much function can be restored with the stem cell treatments presently in clinical trials.
The spinal cord is the delicate tissue encased in and protected by the hard vertebrae of the spinal column. Together the brain and spinal cord form the body’s central nervous system.
The spinal cord is made up of millions of nerve cells that carry signals to and from the brain and out into other parts of the body. The information that allows us to sit, run, go to the toilet and breathe travels along the spinal cord.
The main cell type found in the spinal cord, the neuron, conveys information up and down the spinal cord in the form of electrical signals. An axon (also known as a nerve fibre) is a long, slender projection of a neuron that conducts these signals away from the neuron's cell body. Each neuron has only one axon, and it can be as long as the entire spinal cord, up to 45cm in an adult human.
The axons that carry messages down the spinal cord (from the brain) are called motor axons. They control the muscles of internal organs (such as heart, stomach, intestines) and those of the legs and arms. They also help regulate blood pressure, body temperature, and the body’s response to stress.
The axons that travel up the cord (to the brain) carry sensory information from the skin, joints and muscles (touch, pain, temperature) and from internal organs (such as heart and lungs). These are the sensory axons.
Neurons in the spinal cord also need the support of other cell types. The oligodendrocyte, for example, forms structures that wrap around and insulate the axon. Called myelin, this insulating material helps the electrical impulse to flow quickly and efficiently down the axon.
Spinal cord injuries (SCI) are devastating and debilitating conditions affecting people all over the world, particularly young adults. They are associated with severe physical, psychological, social and economic burdens on patients and their families. To develop effective treatments for SCIs, a precise understanding of the main events following the injury and how these events interact is needed.
Spinal cord injuries generally involve two broad chronological phases that are sustained by the primary and secondary mechanisms of injury. Primary injuries include shearing, laceration, and acute stretching. Acceleration–deceleration events can also cause spinal cord injury, but very rarely lead to complete disruption of the spinal cord.
At a cellular level, axons are crushed and torn, and oligodendrocytes, the nerve cells that make up the insulating myelin sheath around axons, begin to die. Exposed axons degenerate, the connection between neurons is disrupted and the flow of information between the brain and the spinal cord is blocked.
The body cannot replace cells lost when the spinal cord is injured, and its function becomes impaired permanently. Patients may end up with severe movement and sensation disabilities. They will generally be paralyzed and without sensation from the level of the injury downwards. Injuries high in the neck, such as that suffered by Superman actor Christopher Reeve, paralyze the whole body including the arms and shoulders. A common level of injury is just below the ribs, resulting in normal arm function but paralyzed legs. Depending on the location and the extent of the injury patients may suffer complete or incomplete paralysis, and loss of feeling, sexual function and bowel control.
The severity of neurological injury, the level of the injury and the presence of a zone of partial cord preservation are accepted predictors of recovery and survival after SCI. The presence of spared axons crossing the injury site holds great therapeutic potential, and is the basis of a number of emerging therapeutic strategies.
Despite the important advances in the understanding of spinal cord injuries, to date, almost all therapies that have shown promise at the preclinical stage of study have failed to translate into clinically effective treatments. Medical care immediately after the injury – including immobilising and bracing to stabilise the spine - can help to minimise the damage to nerve cells. Rehabilitation can help patients regain physical and emotional independence.
A spinal cord injury is complex, involving different kinds of damage to different types of cells. The environment of the spinal cord changes drastically during the first few weeks after injury (immune cells flow in, toxic substances are released, a scar is formed). A combination of therapies is needed, acting at the appropriate time-point and on the correct targets.
Studies in animals have shown that a transplantation of stem cells or stem-cell-derived cells may contribute to spinal cord repair by:
- replacing the nerve cells that have died as a result of the injury;
- generating new supporting cells that will re-form the insulating nerve sheath (myelin) and act as a bridge across the injury to stimulate re-growth of damaged axons;
- protecting the cells at the injury site from further damage by releasing protective substances such as growth factors, and soaking up toxins such as free radicals, when introduced into the spinal cord shortly after injury.
- Preventing spread of the injury by suppressing the damaging inflammation that can occur after injury
Different cell types, including stem cells, from a variety of sources, including brain tissue, the lining of the nasal cavity, tooth pulp, and embryonic stem cells, have been tested in these studies – mostly conducted in rat models of spinal cord injuries. None of these cells have produced more than a partial recovery of function, but it is an active area of research, and several different types of stem cell are being tested and modified.
Clinical trials using neural stem cells
In December 2010 the Swiss regulatory agency for therapeutic products gave the go-ahead for a StemCell, Inc.-Sponsored Phase I/II clinical trial on chronic spinal cord injury at the Balgrist University Hospital in Zurich (Switzerland). This trial had been inspired by the preclinical evidence of direct oligodendrocyte cell replacement through human neural stem cell (NSC) transplants in early chronic SCI in a particular mouse model. The trial uses a type of stem cell derived from human brain tissue and can make any of the three major kinds of neural cells found in the central nervous system. A single donor can provide eough cells for several transplanted patients). A single dose (20 x 106 cells) of HuCNS-SC is directly implanted through multiple injections into the thoracicspinal cord of patients with chronic thoracic (T2–T11) SCI, and immune suppression administered for 9 months after transplantation. This trial had enrolled patients 3–12 months after complete and incomplete cord injuries. The estimated completion date of this study is March 2016 (clinicaltrials.gov identifier no. NCT01321333). Interim analysis of clinical data to May 2014, presented at the Annual Meeting of the American Spinal Injury Association in San Antonio, Texas has shown that the significant post-transplant gains in sensory function first reported in two patients have now been observed in two additional patients.
The next group of patients currently being recruited in North America (University of Calgary) as well as in Switzerland has included some with incomplete injuries (ie some retained sensory or motor function) (clinicaltrials.gov identifier no. NCT01725880).
Earlier last year, the same company completed enrollment in multicentre open-label Phase I/II clinical titled "Study of Human Central Nervous System (CNS) Stem Cell Transplantation in Cervical Spinal Cord Injury" (clinicaltrials.gov identifier no. NCT02163876). The Pathway Study is the first clinical study designed to evaluate both the safety and efficacy of transplanting stem cells. A total of 52 patients with traumatic injury to the cervical spinal cord are enrolled in the trial. The trial will be conducted as a randomized, controlled, single blind study and efficacy will be primarily measured by assessing motor function according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). The primary efficacy outcome will focus on change in upper extremity strength as measured in the hands, arms, and shoulders. The trial will follow the patients for one year from the time of enrollment.
The hope is that when transplanted into the injured spinal cord, these cells may re-establish some of the circuitries important for the network of nerves that carry information around the body.
Neuralstem began surgeries in a Phase I safety trial of its NSI-566 neural stem cells for chronic spinal cord injury (cSCI) at the University of California, San Diego School of Medicine, with support from the UC San Diego Sanford Stem Cell Clinical Center, in September 2014 (clinicaltrials.gov identifier no. NCT01772810). The FDA amended the Phase I trial protocol to include a total of four patients, as the safety of the same cells and a similar procedure were proven in Neuralstem’s NSI-566/ALS trials. The four cSCI patients, with thoracic spinal cord injuries (T2-T12), have an American Spinal Injury Association (AIS) grade A level of impairment one-to-two years post-injury. This means that they have no motor or sensory function in the relevant segments at or below the injury, and are considered to be completely paralysed.
All patients in the trial will receive six injections in, or around, the injury site, using the same cells and similar procedure as the company’s Amyotrophic Lateral Sclerosis (ALS) trials (the first FDA-approved neural stem cell trial for the treatment of ALS). All patients will also receive physical therapy post-surgery to guide newly formed nerves to their proper connections and functionality. The patients will also receive immunosuppressive therapy, which will be for three months, as tolerated. The trial study period will end six months post-surgery of the last patient, with a one-year Phase I completion goal. An NSI-566/acute spinal cord injury Phase I/II trial is expected to commence in the first quarter of 2015 in Seoul, South Korea.
The Miami Project to Cure Paralysis
The Miami Project clinical researchers currently have several clinical trials and clinical studies available for people who have had a spinal cord injury; some are for acute injuries and some are for chronic injuries. The clinical trials are testing the safety and efficacy of different cellular, neuroprotective, reparative, or modulatory interventions. These include Phase I clinical trials with the patients’ own (peripheral nerve-derived) Schwann cells in both subacute thoracic and chronic cervical and thoracic SCIs and a multicenter Phase II clinical trial with HuCNS-SC in chronic cervical SCIs (as above). All these Miami Project cell therapy trials are recruiting patients (more info on clinicaltrials.gov).
Clinical trials using mesenchymal stem cells
Mesenchymal/stromal stem cells are being investigated as possible treatments for spinal cord injuries. Clinical Trials (clinicaltrials.gov) identifies at present total of 9 trials tagged as MSC trials in spinal cord injuries. These include studies that investigate the safety and efficacy of MSCs derived from the patient’s own bone marrow (5), adipose tissue (fat) (3) or cord blood (1). MSCs are injected in a number of different ways in these trials - including directly into the spinal cord or the lesion itself, intravenously, or even just in the skin, in patients with chronic cervical to thoracic injuries showing ASIA/ISCoS scores between A (complete lack of motor and sensory function below the level of injury) and C (some muscle movement is spared below the level of injury, but 50 percent of the muscles below the level of injury cannot move against gravity).
The hope is that when transplanted into the injured spinal cord, these cells may provide tissue protective molecules/factors and help (indirectly from cell integration and differentiation) to re-establish some of the circuitries important for the network of nerves that carry information around the body.
Clinical trials using embryonic stem cells
California based biotech Geron had a widely reported clinical trial under way for a treatment – the first of its kind – involving the injection of cells derived from human embryonic stem cells. The injected cells were precursors of oligodendrocytes, the cells that form the insulating myelin sheath around axons. Researchers hoped that these cells, once injected into the spinal cord, would mature and form a new coating on the nerve cells, restoring the ability of signals to cross the spinal cord injury site.
After treating four patients with these cells in a phase one (safety) trial, and reporting no serious adverse effects, Geron announced in November 2011 it was discontinuing its stem cell programme. The company said “stem cells continue to hold great promise”, but cited financial reasons for shifting focus to other areas of research.
- More information on this study – press release from Geron about initial trial results
- New York Times news story on the discontinuation of this trial
Following up on the cellular technology initially developed by Geron, Asterias Biotherapeutics has developed a program that focuses on the development of a kind of nerve cell, oligodendrocyte progenitor cells (OPCs) for spinal cord injury. These cells, known as AST-OPC1, are produced from human embryonic stem (ES) cells.
In a Phase 1 clinical trial, five patients with neurologically complete, thoracic spinal cord injury were administered two million hES cell-derived OPCs at the spinal cord injury site 7-14 days post-injury. The subjects received low levels immunosuppression for the next 60 days. Delivery of OPCs was successful in all five subjects with no serious adverse events associated with the administration of the cells or the immunosuppressive regimen. In four of the five subjects, serial MRI scans suggested reduction of the volume of injury in the spinal cord
A second follow up (dose escalation) Phase I/II trial with AST-OPC1 in acute (14-30 days after injury) sensorimotor complete cervical spinal cord injuries (SCI) is currently recruiting participants.
The hope is that when acutely transplanted into the injured spinal cord, OPCs may remyelinate and restore lost functions.
Other clinical trials for spinal cord injuries
- ClinicalTrials.gov contains the most up to date information about current clinical trials, as well as links to result information.
- The European Spinal Cord Injury Federation has a list of clinical trials aimed at the regeneration of the spinal cord and functional repair after spinal cord injury.
- BBC report on follow up of pioneering studies with autologous olfactory ensheathing cells
Outside of the approved clinical trials process, some companies offer stem cell related treatments for patients with spinal cord injuries, without significant evidence that the treatments they offer have been successful. Anyone considering paying for such a treatment is encouraged to discuss it with their physician, and to read this information document prepared by a group of spinal cord injury doctors:
No. Although stem cells are already very useful in SCI research, and are beginning to be tested in cinical trials, there are currently no proven and approved stem cell treatments available for spinal cord injuries. Several different approaches and types of stem cells are being investigated for their potential use in future treatments. Depending on the type of stem cell and the way it is implanted, the aim of the various strategies is to bridge the injury so that axons can regenerate, to replace lost myelin, and to protect the cord from spreading damage after the injury. It is likely that we will see further clinical trials based on these strategies.
- This fact sheet was created by Kate Doherty and reviewed by Stefano Pluchino.
- Thanks also to James Fawcett, reviewer of an earlier version of this fact sheet.
- Some content is based on the spinal cord injury information in the resource Ready or not? A role play on taking stem cells into the clinic
- Lead image by Wellcome Images. Drawings by Cameron Duguid. Neurons by Joshua Bernstock, Dept of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge (UK).