Widespread coverage has been given to the first official clinical trial of stem cells in humans. Many newspapers reported that a patient who was partially paralysed as a result of a spinal injury has become the first to be treated with stem cells in this way.
The landmark study is the first to be approved by the US regulatory body, the Food and Drug Administration, to use human embryonic stem cells on patients in the US.
The Phase I pilot trial is being carried out by a biotech company called Geron, based in San Francisco. The trial’s main aim is to assess the safety of cells developed from human embryonic stem cells (hESC) in patients who have had a recent spinal cord injury (within 14 days). The trial’s other aim is to see whether there is any return of movement or feeling in the patient’s lower body in the year after injection with the stem cells.
What are stem cells?
Stem cells can develop into different types of cell, depending on the chemicals they are exposed to during development. There are three types of stem cells:
- adult stem cells
- human embryonic stem cells (hESC)
- induced pluripotent stem cells (cells that are genetically modified to make them capable of developing into various cell types)
This trial is using a hESC cell line (cells that have all been grown from the same cell(s). The hESCs were taken from surplus fertilised embryos that had originally been created for an in vitro fertilisation (IVF) procedure, then donated for research by the parental donors.
hESC cells differ from other naturally occurring stem cells as they can divide endlessly in tissue culture (and so are often referred to as ‘immortal’). This means that a bank of these cells can be built up without having to harvest new cells from embryos. Human ESCs can develop into any of the more than 200 different types of cells that make up the human body.
These researchers have induced the hESC cell line to differentiate into seven different types of functional cells by growing the cells under different tissue culture conditions. One of these cell types is the one used in this study.
How is the treatment supposed to work?
This trial was of a type of stem cell called “oligodendrocyte-precursor cells”. The researchers have called their version of these precursor cells, GRNOPC1 cells, which develop into oligodendrocytes.
Oligodendrocytes are cells that are involved in the nervous system and have several functions. One of these is to produce myelin (insulating layers of cell membrane), which wraps around neurones, insulating them and allowing them to conduct electrical impulses. Without myelin, many nerves in the brain and spinal cord do not work properly. Oligodendrocytes also release chemicals that enhance neuronal survival and function.
In spinal cord injury, oligodendrocytes are lost, resulting in the loss of the insulation of neurones and the loss of neurones. This leads to paralysis in many patients with spinal cord injuries.
By injecting GRNOPC1 cells into injured areas of the spine that have lost oligodendrocytes, the researchers hope the stem cells will restore (‘remyelinate’) neurones and stimulate nerve growth, leading to restored function and feeling in paralysed areas.
What is the aim of this trial?
The main aim of this phase I trial is to assess the safety of the treatment. In phase I trials, a small number of patients are exposed to the treatment and monitored closely to assess side effects and rejection of the cells by the body.
In order to monitor safety outcomes in this trial, patients will be followed for a year after the cells are injected. The patients will be monitored for a further 15 years after the administration of GRNOPC1 cells.
The trial’s other aim is to see whether there is any return of movement or feeling in the lower body in the year after injection with the stem cells.
Who is eligible for the trial?
There are specific criteria for inclusion in this trial. These include:
- The spinal injury must have been severe enough to have caused paralysis, but the nerve fibres within the spine must still be intact. The researchers say that most spinal injuries are “contusions (bruises)” to the cord rather than a severance of the nerve fibres. In this trial, the injury cannot result from penetrating trauma (such as an injury that severs the spinal cord).
- Patients must have sustained their injury within the last 14 days. Animal studies have shown that GRNOPC1 injections are ineffective if given more than three months after injury because of scarring that occurs in the spinal cord.
- The injury must occur in the patient’s back (at neurological level T3 to T10) rather than further up the spinal cord. Damage at higher areas of the spinal cord lead to different severity of paralysis – for example, paralysis of the legs and arms. Whereas an injury further down the back in the thoracic area (neurological level T3 –T10) may cause paralysis in the legs but spare the arms.
- Patients must have only one severe spinal injury, with complete loss of movement and feeling below the site of the injury. Most patients do not recover from injuries of this severity.
- Patients with other organ damage or disease that would compromise the safety of the surgery or the immunosuppressant drugs that form part of the treatment.
Where is the trial taking place?
At several institutions in the US. This patient was enrolled at Shepherd Center, a spinal cord and brain injury hospital in Atlanta, Georgia. Patients are also being enrolled to the trial through Northwestern Medicine in Chicago, Illinois. In total, seven candidate medical centres in the US may participate in the trial.
Will treatment be extended to other spinal injuries?
"After safety is demonstrated in the initial group of subjects, Geron plans to seek FDA approval to extend the study to increase the dose of GRNOPC1, enroll patients with complete cervical injuries and, ultimately, expand the trial to include patients with severe, incomplete (AIS grade B or C) injuries to test the safety and utility of GRNOPC1 in as broad a range of severe spinal cord-injured patients as medically appropriate."
Have the cells been tested before?
This is the first clinical trial to look at implanted hESCs for spinal cord injury in humans in the US. Animal studies in rats with injured spinal cords showed that the animals regained some movement following injection of the GRNOPC1 cells.
These pre-clinical studies also gave some reassurance to concerns that benign growths of unwanted cells may form from the injection of therapeutic cells. It also reduced concerns that there may be increased sensitivity to pain associated with the treatment, or the body may generate an immune response against the cells. The animal studies showed that there was no unwanted cell growth. However, they did observe cysts at the injury site. The treatment did not affect the animals’ pain responses, nor did the cells cause a major immune response. These experiments were conducted over the course of one year.
Why is there controversy?
The controversy arises from the use of human embryonic stem cells. BBC News points out: “opponents argue that all embryos, whether created in the lab or not, have the potential to become a fully fledged human, and as such it is morally wrong to experiment on them”.
The manufacturers argue that the embryos were surplus from IVFs procedures, and would otherwise have been destroyed. They were donated by the parents for research under informed consent. Opponents to using these cells suggest that adult stem cells should be used instead. The manufacturers argue that they can grow many cells from one embryo source.
When will the trial finish?
The trial will follow up the participants for one year, monitoring side effects and assessing whether there has been any functional improvement over this period. The patients will be monitored over the next 15 years to assess any possible long-term side effects.