ARTICLE IN BRIEF
The FDA has approved a small clinical trial to begin testing the safety of GRNOPC1, an oligodendrocyte (spinal cord) human embryonic stem cell therapy that has shown promise in stimulating nerve growth and remyelination in animal models of spine injury.
The Food and Drug Administration on Jan. 21 approved the first clinical trial to assess the safety of therapeutic embryonic stem cells in human subjects.
Geron Corp., of Menlo Park, CA, was granted an investigational new drug application to begin testing GRNOPC1, an oligodendrocyte (spinal cord) human embryonic stem cell (hESC) therapy that has shown promise in stimulating nerve growth and remyelination in animal models of spine injury, allowing some paralyzed animals to move and even walk again.
The Geron cell line predates the Aug. 9, 2001, Bush Executive order that banned government funds for embryonic stem cell lines after that date. Restrictions will remain in place unless rescinded formally by Congress or President Obama, who has pledged to reverse the Bush Administration policy.
The company plans to begin the phase 1 safety study at seven research hospitals, which will be required to seek approval from their respective institutional review boards. The study will include eight to ten people who have subacute, functionally complete injury between the T3 and T10 spinal segments, and will focus on trauma cases only.
Geron spent $45 million to develop the therapy and submitted 22,000 pages of supporting documents to the FDA.
SAFETY CONCERNS, RISKS
Although the study is only designed to assess the safety of GRNOPC1 and its administration by injection, efficacy will also be closely monitored, Geron President and CEO, Thomas B. Okarma, MD, PhD, told reporters during a special online teleconference in January.
“Our primary end-point is safety, but we will also be looking for efficacy in terms of restoration of improved neuromuscular control or sensation in the trunk or lower extremities, including bowel and bladder control,” Dr. Okarma said.
The company chose to focus on thoracic injuries for safety reasons, he said. “We would not want an unexpected toxicity from cells causing a loss of respiratory drive or function,” he said, which could be a catastrophic side effect of the intervention.
There is concern about the risk of teratomas and other tumors, which have occurred in some animal studies of hESCs. However Geron reported that none of the animals in its tests developed tumors. Also, there been no significant migration of injected cells outside the spinal cord, increased neuropathic pain, or systemic toxicity.
The stem cells will be injected into the spinal cord at the injury site within seven to 14 days after injury, because the therapy may not work for older injuries, according to Dr. Okarma.
GRNOPC1 has restored some function in animals with acute spine injuries, but recovery has been somewhat limited, according to a May 2005 study in the Journal of Neuroscience.
In the animal studies, injured spinal cords showed improved axon survival and extensive remyelination of surrounding axons nine months after a single injection. By that time the cells had also migrated and filled the spinal lesion cavity with bundles of myelinated axons.
If safety and subsequent efficacy trials prove successful, the technique could have applications in restoring nerve function in multiple sclerosis, stroke, and other neurodegenerative conditions, Dr. Okarma told reporters.
The FDA's green light was met with both optimism and concern by other stem cell researchers.
“We have to start somewhere,” commented Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California-San Francisco.
“It will be wonderful if it helps patients, but it has only worked in animals so far, and rodents are very different from people — that's the problem. I don't think we can expect to see any dramatic clinical improvement in patients. I expect a modest effect at best.”
What will be gained, however, in addition to assessing safety, is knowledge on how the cells will behave once they are introduced into the body and how the body will respond, he continued.
“Will there be tumors? Will the cells be traceable? These are some of the questions that need answers,” he told Neurology Today in a telephone interview.
“Everyone in this field of research has a stake in the [trial's] outcome. It will either make our work easier or more difficult. I just hope there are no adverse events.”
Evan Y. Snyder, MD, PhD, professor and director of the stem cell and regenerative medicine program at the Burnham Institute in La Jolla, CA, said he and other researchers believe the trial might be premature, posing a major risk to the field in general.
“I don't think most of us in the field see this as a major step, but more of a small, iterative step,” he told Neurology Today in a telephone interview.
The FDA approval is probably more controversial among stem cell scientists than among politicians or the public, he noted.
“We're concerned about whether the technology is ready to go forward in humans. Any safety problems could set the field back, and not just teratomas. Cell overgrowth or migration of inappropriate cell types are also an important concern.”
Above all, he stressed, the public must understand that this is purely a safety trial — efficacy, although it will be widely reported if patients do respond, is not part of the assessment.
“Conversely, and unfortunately, if there are any adverse events, or no improvement, the news will likely be viewed by the public as a failure of the technology — that stem cells do not work. This might be unavoidable.”
There has also been a lot of scientific debate over whether the procedure should have been tested in a large animal model before human subjects, he noted.
“What is in the back of everyone's mind in the stem cell community is what happened with gene therapy, where overzealous researchers made mistakes that resulted in the highly-publicized death of one patient. That mistake set the gene therapy field back two decades, and we don't want the same thing to happen with embryonic stem cells.”
He also noted that institutional review boards can be more conservative than the FDA in approving clinical trials involving unfounded techniques, and Geron may have problems finding medical centers willing to take on the risk of a trial.
“What I think will happen now is that everyone will wait and watch these patients for one or two years. I don't think any other embryonic stem cell trials will be approved by the FDA until we see what happens in these patients,” he said.