“The idea is to start conservative, with the worst patients who have the most to gain and the least to lose.”
The Company Who Cried Clinical Trial,” blazoned a headline on Wired magazine’s blog network this summer, with the blogger calling attention to how often Geron has said it was on the verge of a first-of-its-kind clinical trial that entails transplanting a type of neural cell into spinal cord-injured patients.
Even so, and with Geron researchers now saying the trial will begin in 2008, no one is tuning them out. Anticipation remains strong, not only because of what the test could portend for spinal cord repair, but because success would represent, according to Menlo Park, California-based Geron, the first time a product derived from embryonic stem cells (ES cells) has proved safe and effective for humans. This would be a boon for those who want to ease restrictions on federal funding for ES cell research. Should the trial fail, however, it could be a major setback for ES cells and the many labs hoping to channel them into countless therapies.
Such a product doesn’t come cheap. The investigational new drug application (IND) that Geron expects to file by year’s end will be some 20- to 30-thousand pages long. “Granted, this IND is larger than most,” notes Anthony Davies, Geron’s vice president of product development, “but that’s where the bar is, in terms of getting products into the clinic,” especially a product meant for the tricky confines of the spinal cord.
The research is part of Geron’s much larger, multiyear, human embryonic stem cell program, into which the company has sunk more than $100 million. Notes Davies, “This is biology; the raw materials are complex and expensive. This is the first time we”—or possibly anyone—“has tried to manufacture human embryonic stem cells under GMP [Good Manufacturing Practice Regulations] to meet FDA requirements.”
Geron has no products for patients yet, and the only return on investment to date comes from marketing its assay kits and selling cell lines through licensees. Still, Reni Benjamin, a research analyst at New York-based Rodman and Renshaw, remains optimistic about several prototypes inching through Geron’s pipeline. They include six different cell types that are slated for transplant therapies, respectively, for cardiovascular, central nervous system, pancreas, liver, and bone and joint disorders. Each cell type is derived from embryonic stem cells.
“Geron is master of its domain,” observes Benjamin. “It’s been a leader in the stem cell space for quite some time, has been slowly making headway, and has been able to successfully raise money from investors repeatedly, such that now it has a cash hoard of about $217 million.” Benjamin projects that, on the heels of a net loss of around $31 million last year, Geron this year will burn through another $42 million. The company needs to spend money, he allows, if it’s to attain its goal of becoming a commercial drug company that manufactures off-the-shelf cell therapies for entire patient populations—no small undertaking when you consider that, in the area of spinal cord injury alone, there are as many as 50,000 new cases worldwide.
China by itself is fueling demand for spinal cord intervention, notes Wise Young, the director of the W.M. Keck Center for Collaborative Neuroscience at Rutgers University. In 1995, a study of spinal cord injuries in Beijing, its rural surroundings, and Shanghai recorded only five cases per million people in a year in comparison to the United States’ 35 cases per million. Ten years later, a survey in the same regions in China counted a 10-fold increase in spinal cord injuries, to 65 cases per million. “I think China’s incidence in 1995 was much lower because people probably died before reaching tertiary care centers,” says Young, “and also because there was so little travel by motor vehicle.”
Motivated by the need for effective therapies, Young, in conjunction with the China Spinal Cord Injury Network, also has plans in 2008 to test a cell therapy in spinal cord-injured humans. Their approach will attempt to regenerate severed neurons by means of injecting umbilical cord blood stem cells and lithium, a drug known to stimulate the proliferation of cord cells.
Geron’s approach does not try to repair the spine’s severed nerve cells. Instead, it attempts to restore the benefit of myelin, the fat-like material that wraps around and insulates nerve cells’ axons, the long fibers that connect the cord to different parts of the body. Injury to the cord is accompanied by a significant loss of the myelin sheaths, rendering axons incapable of conducting signals between brain and muscles. The body’s oligodendrocyte cells, a type of neural cell, produce myelin, and so Geron’s plan is to remyelinate denuded axons by putting oligodendrocyte progenitor cells (OPCs) into the site and letting them do their thing, a strategy that might restore at least a modicum of spinal function. (OPCs are simply immature precursors of mature oligodendrocytes.)
When Geron was founded in the early 1990s, hardly anyone imagined mending an injured spinal cord. The company’s early mission—one conceived by Geron’s then-CEO Michael West—was to outsmart human aging. Toward that end, Geron’s scientists went in search of telomerase, the protein responsible for making a cell’s telomeres, the ends of chromosomes that appear to play a role in a cell’s aging process. Put telomerase into cells and it might lengthen telomeres as well as a person’s life. Inhibit telomerase, and you possibly might slow the reckless division of cancer cells.
Geron today has two telomerase drugs undergoing clinical trials—a vaccine and an inhibitor both aimed at cancer cells—and is researching how drugs that activate telomerase might counter the effects of aging and associated degenerative conditions.
Mouse ES cells had been isolated in the 1980s, and West came to realize that he might achieve his goal using those cells, if only they could be harvested from human embryos. In 1995 Geron began funding Jamie Thomson at the University of Wisconsin for that work and three years later, in May 1998, Geron received a call from Thomson saying he had succeeded. By that time, West had left the company, later taking up the reins at Advanced Cell Technology on the opposite coast. Thomas Okarma has headed Geron ever since.
Over the next two years, Geron’s gene therapy program, aimed at placing telomerase into cells, lost momentum. “The blush of gene therapy eroded away due to numerous problems,” says Jane Lebkowski, Geron’s senior vice president of regenerative medicine. Gene therapy everywhere slowed to a crawl when an 18-year-old patient named Jesse Gelsinger died after receiving gene therapy for a rare liver disorder at the University of Pennsylvania. During the same period, Geron’s stem cell program got stronger and stronger.
“I would have predicted Parkinson’s disease was going to be our first goal,” Lebkowski says today. The protocol seemed straightforward enough: Grow ES cells; steer them to yield dopamine-producing cells, the brain cells ravaged by Parkinson’s; and then transplant those cells into the appropriate brain regions. Researchers transplanting stem cells into Parkinson’s animal models weren’t demonstrating “terribly good results,” however, Lebkowski recounts. That’s when a new partnership emerged, along with a new direction in research.
Hans Keirstead at UC Irvine’s Reeve-Irvine Research Center was getting positive results when he implanted OPCs into the spinal cords of rats. Keirstead, a neurobiologist who did his postdoctoral training at Cambridge University, is one of the scientists who originally demonstrated that injury to the spinal cord is accompanied by a significant loss of the myelin that sheathes axons. He realized that no matter how many neurons had been severed at the injury site, axons off to the side sometimes escaped injury, although they were missing their myelin and couldn’t function. Hence Keirstead’s goal of re-sheathing them. It wasn’t long before Geron formed a working relationship with Keirstead, whose lab ended up the glad recipient of funds from both Geron and the University of California’s grant-matching BioSTAR program.
Results from testing their OPCs on lab rats with paralyzed hind limbs “are big enough to spur you on to humans,” says Lebkowski. Before treatment, they drag their hind legs. When injected with human OPCs seven days after the injury, they can plant their hind legs and support themselves as they move about. Scans of the animals validate that axons denuded of myelin have indeed been re-sheathed, says Gabriel Nistor, a postdoctoral researcher in Keirstead’s group. Remyelination isn’t the only factor that appears to benefit the rodents. The transplanted cells, Nistor says, also “secrete growth factors that can rescue some neurons from dying.”
Previous work on “shiver mice”—mice in which a deficiency of myelin causes a shivering-like tremor—gives credence to this approach, as well. When human oligodendrocytes are injected into these animals, their missing myelin is replaced with human myelin and the mice stop shaking.
Geron’s expectations for its human trials are fairly modest. “What we’re looking for isn’t necessarily that everyone is going to get up and walk,” notes Lebkowski. “But if you could improve even just one level of spinal function, especially in someone with a cervical [neck] injury, it could make a big difference.” Reducing a patient’s impairment by just one spinal column segment might re-establish some small hand or arm movement, restore a bit of bladder control, or improve some portion of heart or lung function. It’s been said about Christopher Reeve, for instance, who sustained his injury high in the cervical region, that had he regained one level of function, he might have been able to dispense with his ventilator.
To convert ES cells into OPCs, the scientists follow a 42-day protocol. The ES cells they start with come from Jamie Thomson’s very first cell line. The concern that these early cell lines might be contaminated because they were made with mouse feeder cells, Lebkowski says, is unwarranted. “As soon as Jamie’s cells arrived, we tested them for any pathogens that could have come from mouse feeder cells and any other agents they might have been exposed to,” she recounts. “We asked ourselves, ‘Are these cells suitable for human use? Are we going to pour millions of dollars into developing these cell lines for clinical use?’” The cells passed all their tests, and Geron subsequently developed a method that enables embryonic cells to be grown in the company of human, not mouse, feeder cells, thus avoiding any suspicion of pathogen contamination.
Up to 30 patients will participate in Geron’s Phase 1 trial, each one a “complete” patient, meaning someone with total paralysis. “The idea is to start conservative, with the worst patients who have the most to gain and the least to lose,” says Lebkowski. A transplant’s timing will be tremendously important, the researchers believe, since their animal studies indicate that cells need to be inserted into the spinal cord between seven to 14 days after an injury occurs. If they are implanted any earlier, the notorious inflammation that occurs immediately following a spinal injury might destroy the cells; any later, and scarring might impede their ability to reach those axons that need rewrapping.
Patients initially will be injected with 1 million cells, and if no toxic effect occurs, the doses will be increased up to 20 million cells. Geron has evidence that its OPCs do not trigger a recipient’s immune response. Still, to be on the safe side, the researchers will administer immunosuppressive drugs to their patients. For the purpose of injecting the cells, Geron has designed a special syringe and syringe holder that will allow a surgeon to release cells into the spinal cord at a defined depth for a set period of time without the cells squirting back out. These devices will require the U.S. Food and Drug Administration’s signoff, as well.
Geron’s pre-clinical animal studies have dragged on, says CEO Tom Okarma, primarily because of the large number of animals—some 2,000—in which Geron has had to test its OPCs. “What surprised us the first time we had a conversation with the agency,” says Okarma, “was how high the bar was going to be, in terms of numbers of animals and the length of time we had to keep the animals alive.”
“There are a number of unique things about this IND,” notes Okarma. “First of all, it’s almost unprecedented when the sponsor of an IND, in this case Geron, is the only producer of peer-reviewed literature that speaks to the technology being regulated. All the publications on glial cells in spinal cord injury made from human ES cells are Geron’s. The publications in the literature from non-Geron scientists are contaminated from bad results, because no one knows how to grow these cells the way we do.” When other researchers transplant their cells into animals, they report a high frequency of tumor formation, says Okarma, which the FDA “must obligatorily examine when they look at our application. So because of all that noise in the literature, the bar is higher.”
The fact that no clinical studies have ever been done with derivatives of embryonic cells makes ruling out a whole host of safety issues—from whether the cells will spawn tumors or migrate to the wrong places in the spinal column—all the more necessary, says Anthony Davies, especially since these cells could serve as the foundation of an entire new template for pharmaceutical products.
“These are the very early days,” says Susan Howley, director of research for the Christopher and Dana Reeve Foundation, which allocates only about 10 percent of its funds to stem cell-related projects. “It’s not that we don’t believe in stem cells, but simply because, from the perspective of our individual grants program, many of the projects we have seen have lacked scientific rigor, or they’ve been good, substantial science, but have been so basic and so removed from spinal cord application that they are more appropriately funded at the NIH level.” Howley admits, however, that someone has to go first.
“We don’t know if cell therapies will restore function to patients,” notes Wise Young, “but what we do know is that we need to set up the infrastructure to be able to test different kinds of cells.”
Ann Parson is the author of The Proteus Effect: Stem Cells and Their Promise for Medicine, which was chosen by Library Journal for its yearly list of best science books for general readers.