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Race to Human Stem-Cell Trials

| Source: wired.com

SAN DIEGO — Several scientists have used embryonic or fetal stem cells to help rodents with spinal cord injuries walk again. The researchers travel the country showing videos of rats dragging their hind legs, followed by clips of them miraculously hopping around following stem-cell injections.

The question now, especially in the minds of the 250,000 people in the United States with spinal cord injuries, is: When will the research transfer into helping humans? The answer depends on who you ask. Some scientists believe it could happen as soon as the end of this year. Others say that’s too soon, and data from larger animals such as dogs or monkeys is necessary before researching with humans.
Evan Snyder of the Burnham Institute in La Jolla, California, is one of those video-toting researchers. Last week at a small stem-cell conference here, he showed the dramatic improvement (.mov) in rats he achieved in 2002.

Despite those positive results with rats, Snyder believes more work must be done before doctors try the experiment on humans. The controversy surrounding embryonic and fetal stem-cell research means the first human clinical trial using the cells will be under a microscope in more ways than one, he said. If something goes awry, opponents of killing embryos for research will be poised to quash future research.

“The last thing we need is another Jesse Gelsinger,” Snyder said, referring to the 18-year-old man who died during a gene-therapy trial at the University of Pennsylvania in 1999. After Gelsinger’s death, the Food and Drug Administration closed many gene-therapy trials around the country.

Stem cells have the unique potential to self-renew, and to become various cell types. Researchers believe those taken from embryos to be the most flexible kind. Adult stem cells, derived from bone marrow, blood, skin, hair follicles, nasal passages and the brain, come without the ethical quandary, but some scientists doubt they have as much potential as embryonic stem cells.

In 2001, President Bush declared that no federal funds could be spent on embryonic stem-cell lines developed after that date. Since then, many states have taken on funding efforts, but most of the work mentioned in this story was funded privately.

Researcher Hans Keirstead, who also has helped rats with spinal cord injuries to walk again, isn’t convinced that primate studies are necessary before testing in humans. Some scientists believe human stem cells are more similar to rodents than monkeys, he said. Keirstead, an assistant professor of anatomy and neurobiology at the Reeve-Irvine Research Center, said he will publish his research soon in a scientific journal.

“Are we going to learn anything from the monkey studies?” he said. “If so, then yes, we should do them. If not, then it’s a waste of time and a delay for getting into humans.”

Keirstead has been criticized by fellow researchers for hyping his research and moving too fast. But he said patient safety and being honest with patients about potential outcomes are his top concerns.

Geron, a publicly traded stem-cell company, is performing studies that could lead to an Investigational New Drug application with the FDA based on Keirstead’s research, which the company funded1. An IND application is the first step to beginning a clinical trial.

Thomas Okarma, Geron’s CEO, is even less convinced that larger animals are necessary before testing Keirstead’s technique in humans. During an interview at the conference, he said he believes the clinical trial could begin in mid-2006.

Some scientists believe that time frame is too aggressive for the study, which most likely would center on recently injured patients (about a week post-injury), since researchers haven’t yet seen success in animals with chronic injuries.

“I think that Geron is offering an optimistic time frame, which is what public companies sometimes do when they haven’t ever done a clinical trial before,” said Jeanne Loring, adjunct associate professor in stem cells and Regeneration at the Burnham Institute.

Geron’s Okarma, however, cites two of Keirstead’s Geron-funded studies as a foundation for human trials. One treated the “shiverer” mouse, which lacks the protective coating around its nerves called Myelin, causing it to shake. Keirstead’s stem-cell therapy calmed the shivers.

The second is Keirstead’s success in treating rats with spinal cord injury, or SCI, videos of which he revealed to the public in 2002. The work will appear “within weeks,” Okarma said, in the journal Neuroscience.

“We’ve shown it works in two different models: the shiverer mouse and the SCI rat,” Okarma said. “So what if you showed it in the monkey or a cat where frankly the science is not validated? Plus, no one wants to make monkeys spinal-cord injured.”

Keirstead said he is performing further research to determine whether larger animal studies should be done, “but it’s incorrect to say monkey work is necessary for every single therapy.”

Meanwhile, the FDA’s main concern is the potential toxicity of the therapy, according to Okarma.

Geron’s pre-IND studies include six- to 12-month toxicity studies in mice and rats, he said. When they are complete, he hopes the FDA will grant approval to move the research into human subjects. He emphasized he has no interest in rushing into a study that might be unsafe, but unnecessarily delaying a therapy would be just as tragic.

“The world spotlight is going to be on this and the last thing we want to do is make patients worse,” Okarma said. “So we’re turning every stone over to rule out ways in which these cells could be harmful — as well as to optimize a production scheme to find the cell types that are ultimately likely to be beneficial.”

Some researchers, like Snyder, don’t believe spinal cord injury should be the subject of the first human embryonic stem-cell trial. His lab is working on other projects, including ways to engineer stem cells to home in on brain tumors, as well as treatments for amyotrophic lateral sclerosis (or Lou Gehrig’s disease), conditions he believes would be more appropriate targets for the first human applications.

Snyder said he and Keirstead are friends, and they have discussed combining their approaches to spinal cord injury. Still, Snyder takes a more conservative approach. He believes trying to rewire the entire spinal cord is too complicated at this point in the research, and a clinical trial would need to have very modest end points or risk being a big disappointment.

“For example, if someone had C6 injury, and I was able to buy him function down to C7,” Snyder said, the patient would benefit. “If you had even bought Christopher Reeve an extra segment of spinal function he would be off his Ventilator. He would not be running a marathon, but you’ve changed his life.”

Scientists at Advanced Cell Technology, another publicly traded company, are also moving toward clinical trials with retinal cells derived from embryonic stem cells. Dr. Robert Lanza, Advanced Cell’s vice president of medical and scientific development, said he hopes to be engaged in human clinical trials “in a couple of years.”

Other ailments are also in the running to become the subject of the first embryonic stem-cell clinical trial, said Advanced Cell’s president and chief scientific officer, Michael West. Blood diseases such as AIDS, anemia and cancer — as well as skin and hair transplants — could be low-hanging fruit for stem-cell therapies, West said. However, West would not confirm whether Advanced Cell has programs in those areas.

Doctors in other countries, including Portugal, China, Australia and Russia, have forged ahead with some success using both adult and embryonic stem cells in spinal cord injury patients.

But in the United States, it’s not up to the scientists to decide when they can begin human clinical trials. The FDA must approve three levels of clinical trials in order for any therapy to move forward. The agency then decides if doctors can prescribe the treatment based on whether the data shows the potential benefits outweigh the risks.

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