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Paralyzed with 7-14 Days to Decide on a Test

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In January 2009, Geron, a biotechnology company located in Menlo Park, California, got FDA clearance to inject spinal cells derived from human embryonic stem cells into paralyzed patients.

This is the first time a stem cell based therapy will be assessed objectively — that is, as part of a clinical trial — in human beings. As early as this summer, eight to ten patients with spinal cord injury will be selected to participate. This trial raises ethical concerns and UCSD philosopher Mary Devereaux led discussions about them at The Fleet Center and at the UCSD Medical School.

Professor Devereaux brought several questions to the table. First, what makes getting an injection of spinal cells derived from human embryonic tissue different from getting, for example, an injection of bone marrow cells from a donor?

Second, given the physical and emotional trauma of patients recently paralyzed, can they fully grasp the risk they accept when they agree to have Geron’s spinal cells injected into their bodies? Third, does the Geron trial requirement for injection of the stem cell product within seven to fourteen days of injury raise further concerns?

GRNOPC1 Injection
The goal of embryonic stem cell research is to start out with a bank of cells that has the potential to grow or “differentiate” into almost any cell in the body and to orchestrate those cells to become one cell type — in this case, a cell found in the spinal cord, an oligodendrocyte. The job of oligodendrocytes is to provide support to neurons; they do so in two ways. They produce molecular messengers that promote neuron health and myelin, an insulating material, that wraps the long fibers (axons) of neurons. Myelin allows neurons to conduct electrical messages speedily. During spinal cord injury, the loss of myelin contributes to loss of nerve function. The end result for many patients is paralysis.

Geron researchers have patented a way to differentiate human embryonic stem cells into oligodendrocyte progenitor cells. “Progenitor cells” are most of the way down the road to differentiation; they will complete the process once inside the body. Geron also holds a patent for manufacture of these cells into vials ready for distribution to hospitals and injection into patients.

This population of living oligodendrocyte progenitor cells makes up their “GRNOPC1” product.

Geron is conducting a small trial in which GRNOPC1 will be injected into the injury site of patients that have sustained spinal cord injury. The groundwork for this human trial is research conducted in rats in Professor Keirstead’s laboratory at the Reeve-Irvine Research Center.

This research, partly funded by Geron, was published in 2005 in The Journal of Neuroscience. The Keirstead group severed the spinal cords of rats and then either seven days or ten months post-injury injected the injury site with GRNOPC1. The rats injected at seven days showed improved locomotion; the rats injected at 10 months did not. Eight weeks after injection, the rats were sacrificed and tissue slices of the spinal cords confirmed that the GRNOPC1 cells had indeed completed differentiation into oligodendrocytes and, along with remyelinated axons, had filled the spinal defect.

The spinal cords of the rats injected at 10 months post-injury did not show this remyelination.

Up to seven U.S. medical centers, all referral centers for neurotrauma, have been selected to participate in the Geron trial. None of the locations have been announced and no patients have been injected to date.

The patients who qualify for inclusion in this Phase I trial have functionally complete thoracic spinal cord breaks — in other words, waist-down paralysis. They will have GRNOPC1 injected into the injury site seven to 14 days after injury. The aim of a Phase I trial is to establish safety of the GRNOPC1 injection, not efficacy. These patients are not expected to recover the ability to move their legs because of this injection.

Technology and Tumors
Blood and bone marrow cells are routinely harvested from donors for use in patients. Geron is able to manufacture the cells that patients need. The donated cells differentiated inside a person as part of our biological development; the manufactured cells differentiated in a test tube using sophisticated technology. Does the origin of the cells make a difference?

Yes. First, products derived from embryonic stem cell banks may be contaminated with undifferentiated cells. This is because not every cell in a bank of stem cells that is induced to differentiate in fact does. Second, of the cells that do differentiate, in vitro or “lab bench” observation reveals that some dedifferentiate over time.

This raises the concern of future tumor growth at the product injection site since undifferentiated and dedifferentiated cells retain/regain the ability to differentiate into any number of cell types. And this is a substantive difference and substantial risk unique to embryonic stem cell derived therapies.

In the case of the Geron’s spinal cells, GRNOPC1, the Keirstead study specifically looked for tumor formation and found none in the injected rats. The lack of tumors was attributed to Geron’s patented technology for producing “high purity” oligodendrocyte progenitor cells.

High purity, however, does not mean 100 percent oligodendrocyte progenitor cells make up the final product. Geron’s literature describes the GRNOPC1 product as “a cryopreserved cell population containing a mixture of oligodendrocyte progenitor cells and other characterized cell types.” There are “other characterized” or contaminant cells in the product. The majority of cells in the product are oligodendrocyte progenitor cells but will they remain so? Might some not revert? The technology for delivering a pure and definitively differentiated product simply does not yet exist. Eight weeks after injection the spinal cords of the sacrificed rats were tumor free. Is it reasonable to expect the same over the relatively lengthy lifespan of a human being?

Are we prepared to have a young man survive spinal trauma and come to peace with life in a wheelchair only to learn, years later, that he has developed a tumor in his spine at the injection site? Are we prepared to accept the backlash that would affect the entire field of stem cell research, not just spinal cord injury research, if poor consequences result from the use of premature technology?

Informed Consent/Seven to 14 Days
Patients abruptly paralyzed are extremely vulnerable to discounting risk and to subscribing to false hope particularly in the immediate aftermath of injury.

These patients might agree to almost anything offered by their doctor without full consideration of long-term possible consequences. Can these patients give meaningful consent to participate in a medical trial?

Patricia Duncan, Data Coordinator for the Shepherd Center in Georgia, a hospital specializing in spinal cord trauma, works on the frontline of patient recruitment for medical trials and reports success.

When informed consent is secured over a series of days with the patient and the patient’s family told plainly that a medical trial is only one of many steps involved in finding a cure and that at this time there is no cure then, in some patients, robust informed consent can be attained.

Is this degree of understanding the risks and benefits of a medical trial possible seven to 14 days after injury? And why this time frame?

The time frame is likely dictated by the pathology of spinal cord injury. Demyelination is only one of three components of spinal cord injury; the second is the formation of a “glial scar” and the third is inflammation.

The scar creates the time crunch. It is primarily made up of astrocytes, another supportive cell in the spinal cord, that physically rearrange themselves into a mesh at the site of injury. This mesh reestablishes the blood-brain-barrier and thereby prevents further inflammation that is toxic to neurons.

In the rat, a glial scar forms within hours of injury and matures after only one week. The scar is a stopgap measure by the body to stem neuron death at the injury site but it also forms a physical and chemical barrier to future axon growth. This scar is often blamed for the incomplete functional recovery of patients that suffer nerve injury.

Scientists do not know the relative importance of each of the three components of spinal cord injury. Geron has a product that promises to address one component, demyelination, but only if that product can get to the injury site before the glial scar matures. Just as the injured body rushes to get that scar laid down to limit its losses; in tandem, the Geron trial participants must hurry too.

They get seven to 14 days to decide whether or not to participate.

The pressure is on. Between the ungrounded emotional state of someone recently paralyzed and the physical necessity to inject the spinal cells within seven to fourteen days of injury, informed consent will be a challenge for the Geron trial. A few special patients probably will be able to meet the challenge though.

A concern persists. Geron’s January news release announced the company’s intention to move forward with “the world’s first human clinical trial of embryonic stem cell-based therapy.”

But was spinal cord injury the right trial to start the world off with?

While it is not uncommon to run a clinical trial on a therapy targeted for the time-sensitive emergency room setting, spinal cells are unusual among other proposed stem cell derived therapies in having this tight time frame and crisis setting. Most proposed stem cell therapies involve chronic diseases, like cirrhosis of the liver or degeneration of joint cartilage.

These chronic disease patients, while dire, would likely not be desperate at the moment of deciding whether or not to participate in a stem cell trial. There also would be no need for a seven-to-14-day window in which to make that decision. Geron’s product line includes not only spinal cells but also liver, heart, pancreatic, bone, and cartilage cells. Might not one of these other cell types have been a more sage choice for the world’s first trial? What pressures existed to push spinal cells to the front of the line?

The Ethics Center meetings are held the first Wednesday of each month at the Fleet Science Center in Balboa Park at 5:30pm and are open to the public .

The Tough Cases seminars are held on the fourth Tuesday of each month at the UCSD Stein Clinical Research Building at 12 noon and are open to medical students and healthcare professionals interested in medical ethics.

By Vanessa S. Flores, V.M.D., MA.

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