Just over a month ago, on November 14, orderlies at Doernbecher Children's Hospital in Portland, Ore., wheeled a six-year-old child with an incurable disorder of the nervous system into an operating theater. During the next eight hours surgeons used computers to guide a surgical procedure the likes of which the world has never seen: injections of neural stem cells directly into the brain of a human subject.

In this phase I clinical trial, doctors affiliated with Oregon Health Sciences University (OHSU) are collaborating with scientists at Stem Cells, Inc., a company based in Palo Alto, Calif. Their immediate goal is limited to healing children afflicted with Batten disease, a rare but fatal neurodegenerative disorder. In the coming decades, however, this work could lead to treatments for neurodegenerative disorders that affect millions, such as Huntington's, Alzheimer's and Parkinson's diseases.

Batten Disease--A Disorder with No Cure

Batten disease is known to experts as neuronal ceroid lipofuscinosis, or NCL. "NCL patients lack an enzyme responsible for breaking down complex fat and protein compounds in the brain," says Robert Steiner, associate professor of pediatrics at the OHSU School of Medicine, and the trial's lead investigator. "These materials accumulate and interfere with normal cell and tissue function and ultimately cause cells to die."

The cellular damage takes an awful toll. "In early infancy or in childhood the children develop seizures. If they ever had the ability to walk or speak, they lose those abilities. It affects the eyes and the vision, so they become blind ... death is inexorable," Steiner says.

Scientists at Stem Cells identified a strain of stem cells that produce the enzyme whose absence causes NCL. In the phase I trial that will take place later this year, Steiner and other surgeons will be injecting six children with these cells, in the hope that they will manufacture the enzyme and halt the disease. For a full year after injection, the researchers will monitor the patients' cognition and vision. They will pay special attention to any possible side effects of the treatment.

"This takes center stage as the first clinical trial that uses stem cells to attempt to possibly treat a disease," says Arnold Kriegstein, director of the Center for Regeneration Medicine at the University of California, San Francisco. If successful, the study could pave the way for stem cell therapies to be used on conditions such as Alzheimer's, Parkinson's and stroke. But, he cautions, "the first criterion is to see whether these stem cells will be safe."

The Dangers of Stem Cell Therapy

In some cases, uncontrolled growth of neural stem cells has been linked to malignant brain tumors. The researchers chose fetal neural stem cells--obtained from a company that procures tissue from aborted fetuses with the consent of the mothers--because such cells are unlikely to develop into anything other than cell varieties already found in the brain. If embryonic stem cells were used, they might grow into bone, hair or eye tissue, to disastrous effect.

Cancer is not the only kind of trouble that could occur. "The hope is that these cells will do nothing more than diffuse or distribute themselves and pump out this enzyme," Kriegstein says. "There may be some problems if they start turning into cell types that cause mischief, [such as] nerve cells that might start forming circuits and shifting activity."

As therapeutic agents in the brain, stem cells have several advantages over traditional therapies. The blood-brain barrier blocks many drugs on which doctors might otherwise rely. Stem cells injected past this barrier can migrate to regions where they are needed and develop into new brain cells. Because they can survive indefinitely, there should be no need for repeated surgery. Researchers must, however, tailor therapy to the challenges of each disease.

In the Batten trial, the stem cells are being used for their ability to produce and deliver enzymes, rather than their potential to develop into new neurons. Experts believe that several brain disorders, including Huntington's and Alzheimer's, would benefit from a similar approach in which stem cells would secrete hormones to protect existing neurons from further damage.

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