By Emily Underwood, *Science*NOW

Four young boys with a rare, fatal brain condition have made it through a dangerous ordeal. Scientists have safely transplanted human neural stem cells into their brains. Twelve months after the surgeries, the boys have more myelin — a fatty insulating protein that coats nerve fibers and speeds up electric signals between neurons — and show improved brain function, a new study in *Science Translational Medicine *reports. The preliminary trial paves the way for future research into potential stem cell treatments for the disorder, which overlaps with more common diseases such as Parkinson's disease and multiple sclerosis.

"This is very exciting," says Douglas Fields, a neuroscientist at the National Institutes of Health in Bethesda, Maryland, who was not involved in the work. "From these early studies one sees the promise of cell transplant therapy in overcoming disease and relieving suffering."

Without myelin, electrical impulses traveling along nerve fibers in the brain can't travel from neuron to neuron says Nalin Gupta, lead author of the study and a neurosurgeon at the University of California, San Francisco (UCSF). Signals in the brain become scattered and disorganized, he says, comparing them to a pile of lumber. "You wouldn't expect lumber to assemble itself into a house," he notes, yet neurons in a newborn baby's brain perform a similar feat with the help of myelin-producing cells called oligodendrocytes. Most infants are born with very little myelin and develop it over time. In children with early-onset Pelizaeus-Merzbacher disease, he says, a genetic mutation prevents oligodendrocytes from producing myelin, causing electrical signals to die out before they reach their destinations. This results in serious developmental setbacks, such as the inability to talk, walk, or breathe independently, and ultimately causes premature death.

Although researchers have long dreamed of implanting human neural stem cells to generate healthy oligodendrocytes and replace myelin, it has taken years of research in animals to develop a stem cell that can do the job, says Stephen Huhn, vice president of Newark, California-based StemCells Inc., the biotechnology company that created the cells used in the study and that funded the research. However, he says, a separate study by researchers at Oregon Health & Science University, Portland, found that the StemCell Inc. cells specialized into oligodendrocytes 60 percent to 70 percent of the time in mice, producing myelin and improved survival rates in myelin-deficient animals. So the team was able to test the cells' safety and efficacy in the boys.

Led by Gupta, the researchers drilled four small holes in each child's skull and then used a fine needle to insert millions of stem cells into white matter deep in their frontal lobes. The scientists administered a drug that suppressed the boys' immune systems for 9 months to keep them from rejecting the cells and checked their progress with magnetic resonance imaging and a variety of psychological and motor tests. After a year, each of the boys showed brain changes consistent with increased myelination and no serious side effects such as tumors, says David Rowitch, one of the neuroscientists on the UCSF team. In addition, three of the four boys showed "modest" improvements in their development. For example, the 5-year-old boy — the oldest child in the study — had begun for the first time to feed himself and walk with minimal assistance.

Although these signs are encouraging, Gupta and Rowitch say, a cure for Pelizaeus-Merzbacher disease is not near. Animal studies strongly support the idea that the stem cells are producing myelin-making oligodendrocytes in the boys, but it's possible that the myelination didn't result from the transplant but from a bout of normal growth. Rowitch adds that although such behavioral improvements are unusual for the disease, they could be a fluke. Huhn acknowledges that the study is small and has no control, but he's is still excited. "We are for the first time seeing a biological effect of a neural stem cells transplantation into the brain [in humans]." The most important thing, he says, is that the transplants appear safe. This gives the researchers a green light to pursue larger, controlled studies, he says.

It "isn't the flashiest thing," but demonstrating that it's feasible to transplant these stem cells into children's brains without negative consequences — at least so far — is "extremely hopeful," says Timothy Kennedy, a neuroscientist at McGill University in Montreal, Canada.

Although he's concerned that myelination seen in mouse models might not "scale up" to a disease as severe as Pelizaeus-Merzbacher in humans, Ian Duncan, a neuroscientist at the University of Wisconsin, Madison, describes the study as setting a precedent for translating animal research in stem cells to humans. If you could improve quality of life by targeting key areas of the brain with these cells, he says, "that would be a huge advance."