Spinal cord injuries - how could gene and cell therapies help?

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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. Spinal cord injuries can present in different ways, depending on the region of the spine affected. There is currently no effective treatment. Could gene and cell therapy techniques help?

What do we know?

The spinal cord is a collection of millions of nerve cells (neurons) and their fibres (axons) inside our spine, which 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 clinical studies are testing the safety and effectiveness of stem cells and genetic engineering techniques 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.

What are researchers working on?

Inflammation and toxins released by damaged cells at the site of a spinal injury often cause further harm (secondary injury) 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 their supporting cells that wrap & insulate neurons. Damaging the supporting cells can cause otherwise functional neurons to become dysfunctional or die. Researchers are studying how regenerative medicine techniques might be used to restore or improve the function of neurons and their supporting cells to greatly improve a patient’s chances for recovering function.

What are the challenges?

The major goal of regenerative medicine approaches is to re-connect the injured spinal cord by transplanting nerve cells and supporting cells. However, the spinal cord is a highly organised, complex tissue. Precise re-connection of injured spinal cord by transplanting stem cells to restore its function is a huge challenge.

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, and diminished regenerative response from injured nerve cells, can hinder the effectiveness of a treatment.

It isn’t yet clear how much function can be restored with the treatments currently being investigated in clinical trials.

About the spinal cord

The spinal cord is contains millions of nerve fibres and cells which enable communication between the brain and the rest of the body. This communication allows us to sit, run, go to the toilet and breathe. This delicate tissue is 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 (CNS).

How does the spinal cord work?

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. An axon 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 (away 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. For example, cells called oligodendrocytes increase the speed and efficiency of electrical signalling of axons by forming myelin - structures that wrap around and insulate the axon.

Diagram of neuron, showing cell body, axon, and direction of information travel — Neurons transmit information between the central nervous system (CNS) and other parts of the body.

What happens when the spinal cord is innjured?

Spinal cord injuries 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 spinal cord injuries, we need a precise understanding of the main events following the injury, and how these events interact.

Diagram comparing damaged and healthy nerve — **A spinal cord injury affects both neurons and the myelin sheath that insulates axons**

Spinal cord injuries generally involve two broad chronological phases. These are phases relate to the primary and secondary mechanisms of injury.

Diagram showing the different sections of the spine — The spine has different sections. The level of paralysis depends on the location of the injury.

Primary injuries include shearing, laceration, and acute stretching. Acceleration–deceleration events (such as whiplash) can also cause spinal cord injury, but these very rarely lead to complete disruption of the spinal cord.

At a cellular level, axons are crushed and torn. Oligodendrocytes, the cells that make up the insulating myelin sheath around axons, begin to die. Exposed axons begin to degenerate. This disrupts neuron connections and the flow of information along the spinal cord.

The body cannot regenerate the nerve fibres crushed or replace cells destroyed by spinal cord injuries. This is why these injuries often lead to permanent impairments of movement and sensation. Many spinal injuries result in patients being paralysed and without sensation from the level of the injury downwards. Injuries high in the neck (such as the one sustained by Superman actor Christopher Reeve), paralyse the whole body including the arms and shoulders. A common level of injury is just below the ribs, resulting in normal arm function but paralysed legs. Depending on the location and the extent of the injury, patients may suffer complete or incomplete paralysis, as well as loss of motor control, 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 (that is, where the spinal cord has not been severed) are accepted predictors of recovery and survival after spinal cord injuries. The presence of spared axons crossing the injury site holds great therapeutic potential; this is the basis of several emerging therapeutic strategies.

How are spinal cord injuries treated now?

In recent decades, scientists have made many important advances in understanding spinal cord injuries. Despite this, almost all therapies which have shown promise in preclinical studies have failed to translate into clinically effective treatments for repairing the damaged tissue.

Medical care immediately after the injury – including immobilising and bracing to stabilise the spine - can help to minimise the damage to nerve cells. Rehabilitation therapies can help patients regain physical and emotional independence.

How could gene and cell therapies help?

How could stem cells contirbute to spinal cord repair?

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 from damaged tissue, and 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;
Acting as a neuronal relay across the injury to re-connect injured spinal cord
Generating new supporting cells that will re-form the insulating nerve sheath (myelin)
Protecting the cells at the injury site from further damage by releasing protective substances, such as growth factors, and soaking up toxins which are released 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, have been tested in these studies. These studies have used stem from a variety of sources, including brain tissue, the lining of the nasal cavity, tooth pulp, and embryonic stem cells. These studies have mostly been conducted in rat models of spinal cord injuries. None of these studies have yet produced more than a partial recovery of function; however, it is an active area of research, and several different types of stem cell are being tested and modified.

Current research

Clinical trials using neural stem cells

Allogeneic (donated by another individual) neural stem cells are being investigate for their potential in treating spinal cord injuries. Several clinical trials have examined, and continue to investigate, the use of human neural stem cells for spinal cord injuries. These trials injuect neural stem cells dircetly into the spinal cord with the goal the the cells with help re-establish some of the connections between neurons, and create the necessary cells to support both the old and new neurons.

In December 2010 the Swiss regulatory agency for therapeutic products approved a PhaseI/II clinical trial on chronic spinal cord injury at the Balgrist University Hospital in Zurich, Switzerland. This study was sponsored by StemCell Inc. The trial used specific stem cells derived from human brain tissue (neural stem cell or NSCs), which can make any of the three major kinds of neural cells found in the central nervous system. The trial was based on evidence that oligodendrocyte cells were replaced after transplanting human NSCs into a particular mouse model for spinal cord injuries.

For the trial, human NSCs (these specific cells were called Human Central Nervous System Stem Cells or HuCNS-SC) were directly implanted into the spinal cord of patients with complete and incomplete chronic thoracic spinal cord injuries. This trial was officially completed in June 2015.

In 2012 a further Phase I/II clinical study of HuCNS-SC cell transplantation was started with 12 participants and in 2014 another clinical trial was started to test the safety and efficacy of HuCNS-SC transplantation in cervical spinal cord injuries. After having treated 12 patients in the 2012 phase I/II trial and additional 31 in the 2014 phase II trial (total 43 patients), the company reported no serious adverse effects. Stem Cell Inc. prematurely terminated its stem cell programmes in 2016 following an in-depth review of study data. The outcomes appear to have been safe, but were not as effective as the company was aiming for. This reflects the challenges of developing therapies for spinal cord injuries.

In 2014, Neuralstem Inc. began a Phase I safety trial of its neural stem cells (called NSI-566) for chronic spinal cord injury. This took place at the University of California, San Diego, School of Medicine. This trial uses the same cells and a similar procedure as the company’s Amyotrophic Lateral Sclerosis (ALS)/Motor Neurone Disease (MND) trials (which was first FDA-approved neural stem cell trial for the treatment of ALS/MND). The 2014 trial included a total of 8 patients, four of whom had thoracic spinal cord injuries causing complete loss of sensory and motor function. The phase I trial showed safety of transplanted neural stem cells. However, this early study lacked the statistical power and controls needed to evaluate functional improvement. Larger studies would be required to address these questions.

Clinical trials using other neural cells

The Miami Project currently has 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 immunomodulatory interventions. A previous Phase I clinical trial used patients’ own myelinating cells. These were derived from Schwann cells in the patients’ peripheral nervous system. The Miami Project also sponsored a Phase I clinical trial of autologous transplantation (transplantation using the individual’s own cells), using patients’ own Schwann cells to treat chronic spinal cord injuries.

The results of these studies demonstrated feasibility and safety of Schwann cell transplantation. Further studies are needed to gain meaningful functional improvement.

Clinical trials using MSCs

MSCs are also being investigated as possible treatments for spinal cord injuries. Trials are being conducted to investigate the safety and efficacy of MSCs derived from the patient’s own bone marrow, adipose tissue (fat), or cord blood. MSCs are delivered in a number of different ways in these trials - including injection directly into the spinal cord or the lesion itself, intravenously, or even just in the skin. The hope is that when transplanted into the injured spinal cord, these cells provide tissue protective molecules and help to re-establish some of the circuitries important for the network of nerves (indirectly from cell integration and differentiation).

Clinical trials using Embryonic Stem Cells

A Phase I clinical trial by Geron involved the injection of cells derived from human embryonic stem cells (hESCs). This was the first study attempting to treat SCIs using ESCs. 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, which would restore signalling across the injury site.

After treating four patients with these cells in a Phase I clinical 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.

Following up on the cellular technology developed by Geron, Asterias Biotherapeutics developed a program that focused on treating spinal cord injuries with specially developed oligodendrocyte progenitor cells (OPCs). These cells, known as AST-OPC1, are produced from human embryonic stem cells. The hope is that when transplanted into the injured spinal cord shortly after injury (7-14 days), OPCs may re-myelinate damaged nerves, and help to restore lost functions.

In a Phase I clinical trial five patients with neurologically complete, thoracic spinal cord injury were administered OPCs at the site of injury. This procedure was successful in all five subjects and no serious adverse events were associated with either the administered cells or the accompanying immunosuppression regimen. In four of the five subjects, MRI scans suggested a reduction in the volume of spinal cord injury. Further work is needed to confirm the safety and correct dosage of such a treatment.

Unproven treatments

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:

Experimental treatments for spinal cord injury: what you should know