The First Embryonic Stem Cell Trial

Six weeks before the hoopla over President Barack Obama's executive order lifting restrictions on embryonic-stem-cell research, Hans Keirstead, a scientist at the University of California, Irvine, was already sipping champagne. In 2005 Keirstead had published a study showing that a therapy derived from human embryonic stem cells could make partially paralyzed rats walk. Now he'd gotten word that the FDA had cleared the way for Geron, a small biotech company in California, to launch the first clinical trial of the treatment in human beings with spinal-cord injuries. It was incredible news,not just for Keirstead, who'd been wanting to invent a therapy for brain and spinal-cord disorders since he was 11 years old, but for scientists who believe human embryonic stem cells can teach them about complex diseases and potentially lead to cures. Keirstead, 41, and his team of scientists hailed the news over a case of chilled Veuve Clicquot. "We put the last bottle down about six hours later," Keirstead says. "It was just a really fun time."

Opinions about the moral status of an embryo won't change with presidential decrees or FDA decisions, so you can bet that the debate over embryonic-stem-cell research is far from over. But no matter how loud the chatter gets, the science is about to leave the Petri dish. For years, academic researchers have felt stymied by limitations imposed by George W. Bush that allowed federal funding only for research on 21 embryonic-stem-cell lines that already existed. Scientists who wanted to pursue newer cells had to find private dollars, some of which came from state initiatives. Geron, meanwhile, had its own money and was doggedly pursuing its mission to get human embryonic-stem-cell treatments into people. This summer, the company plans to enroll the first of up to 10 patients in a clinical trial that everyoneclinicians, scientists, biotechs, patients, ethicistswill be watching. There is plenty of excitement from people with spinal-cord injuries and their physicians, who can offer little hope for any significant improvement right now. But some scientists are concerned that the research may not be ready for prime time. The simple truth: even if all goes perfectly in the early stage of the trial, which tests for safety, no one with a spinal-cord injury is going to be cured any time soon. Peter Kiernan, chairman of the Christopher and Dana Reeve Foundation, says he is constantly balancing hope against hype among patients. "I feel like I'm in a car turning the steering wheel at the same time that I'm pushing on the brakes."

From the start, Geron's MO has been to put foot to accelator. It is, after all, a company ($200 million in the bank) whose primary goalfor patients and, of course, stockholdersis to get a treatment to market. In 2001 it funded Keirstead's research, which tested a therapy manufactured from human embryonic stem cells (from a Bush-approved cell line), called oligodendrocyte progenitor cells, in rats with a partial spinal-cord injury. When the cells were injected into the damaged area, they restored the spinal cord's insulation, which conducts nerve impulses from the brain to the rest of the body, allowing movement. In Keirstead's study, rats who had 10-month-old injuries didn't improve because too much scarring had developed. But the outcome was striking in animals whose injuries were just seven days old. Two months after treatment, rats who'd lost control of their trunk muscles, tail and hind legsthey could move, but not muchnow exhibited "substantially improved locomotor ability." They could walk.

Nice if you're a rat. Now the company had to figure out how to move the cells into humans. It spent years creating the optimal oligodendrocyte progenitor cell, then focused on how to make a bunch of them identically under strict quality controla process that's a whole lot harder with a living cell than a pill. It even designed a computer-controlled device to position the syringe and control the injection to be sure that the right number of cells went to the right spot. By the time Geron filed its application to the FDA last year, it had 22,500 pages of documentation. Total count: 24 studies, 1,977 rodents, $45 million.

Now Geron is negotiating with up to eight neurotrauma centers to conduct human trials. It will be recruiting people who have injuries in the thoracic, or middle region of the spineparaplegics who are paralyzed from the chest area down. Because the injuries must be newless than 14 days oldthe patients Geron wants to start enrolling this summer are actually healthy people today who haven't yet been injured. But that hasn't stopped the interest among people who are already paralyzed. When the FDA approval was announced in January, Geron's voice-mail system broke down from the flood of calls.

It's not hard to see how important this trial is. Everybody you talk to in the spinal-cord community worries about patients traveling overseas for risky, ambiguous cellular therapies, forking out tens of thousands of dollars and praying for a miracle. Kate Willette, whose husband was paralyzed in a skiing accident eight years ago, understands the desire to get better. Earlier this month she attended a gathering of researchers and the spinal-cord community where she watched Keirstead, dressed in jeans and an untucked white shirt, tell the crowd, "I can't promise you anything, but we're doing our damnedest." Willette, who moderates an online forum for families of people with spinal-cord injuries, says Keirstead is cautious, but exudes a welcome sense of confidence. "I can't tell you how exciting it is," she says of the Geron trial. "Either it's going to work or it's not, but we'll have something to hang our hats on." Of Keirstead, she says: "He's a rock star."

Keirstead's animal research was published in a peer-reviewed journal, but much of Geron's other preclinical documentation has been under wraps; only the company and the FDA know what it says. That leaves some researchers feeling unsettled. What's the precise mechanism of action? Could the cells prompt an immune response in patients? Or generate certain fibers that cause pain? Should Geron perform experiments in other types of animals before they go to humans? John Gearhart, a pioneering researcher whose early stem-cell work was funded by Geron and who is now director of the Institute for Regenerative Medicine at the University of Pennsylvania, says he wants the trial to succeed, but he constantly worries about safety. Gearhart wonders if there might not be some number of cells in Geron's therapy that don't behave as scientists want them tothey don't differentiate themselves into the desired cell type after they're injected. Research has shown that such cells may form tumors or interfere with normal function, and it is difficult to say for sure how many months or years later that might occur. For Larry Goldstein, director of the University of California, San Diego, stem-cell program, a key issue is risk versus benefit. While paraplegia is by no means easy to endure, people do adapt and can have fulfilling lives. What if the treatment causes harm? Ideally, Goldstein would have liked the first human embryonic-stem-cell therapy tested in a disease that leads inexorably to death, like ALS. "I'm nervous," he says. This first trial is "a high-wire act."

Geron's CEO, Dr. Thomas Okarma, says he understands the anxiety. "Nobody wants another Jesse Gelsinger here," he says, referring to the teen who died in a 1999 trial for gene therapy, another pioneering technique. The company, he says, has "lifted stones as far and high as we can to assure ourselves the safety of this product." The
oligodendrocyte cells it is injecting (each patient will receive a syringe of 2 million cells) are "highly characterized," meaning it's seen no evidence of any outliers that might cause trouble down the road. Its tests found no tumors in rodents over the course of a year and no evidence of an immune response (patients will be given immunosuppressants for 45 to 60 days after treatment, but that's to be sure there's no inflammation in the injury site, which might destroy the injected cells).

Patients will be closely monitored with MRIs for the first year and followed for a total of 15 years. And trial volunteers will have complete injuries "with no hope of recovery," making the risk worth the potential payoff, says Okarma. Geron's mantra is "living cells will be tomorrow's pills," he says. And he is confident it will get there. So confident, he believes the oligodendrocyte progenitor cells might be applicable to other nervous-system disorders, like multiple sclerosis, Alzheimer's and stroke. Geron plans to publish more of its preclinical data, Okarma says, but in the meantime, the public should be assured that the company has done rigorous research. "Companies die when they're not successful, when a product is harmful or it doesn't work," he says. "The last thing we want to do is be wrong. The future of the company depends on this." Keirstead, for his part, says the first thing he asks when people say "slow down" is "Do you know anyone in a wheelchair?'"

Everybody wants to be cautious, but researchers, clinicians, patients and biotechs differ on how much risk they can live with and when to pull the trigger. Gearhart says his conservative approach butts up against others in the field. "Every time I say 'be circumspect,' my clinical friends are hitting me upside the head, saying, 'You've got to do it at some point'." That is the view of Dr. Gary Steinberg, a professor of neurosurgery at Stanford, a potential site for Geron's trial. "I'm highly enthusiastic," he says. Steinberg says he has faith in the FDA's review. Without effective treatments currently available, patients with spinal-cord injuries are left with little recourse. "There's a significant unmet need," he says. At the Miami Project to Cure Paralysis, scientific director W. Dalton Dietrich says he has concernsthis is a first, after allbut he also believes researchers will learn a great deal about how to use cellular therapies in humans, something that will help educate and advance the field.

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The First Embryonic Stem Cell Trial