Brain fix: stem cells supply missing enzyme.

Implanted stem cells grew into a range of beneficial brain-cell types and greatly extended the lives of mice missing an important enzyme, researchers report. Furthermore, stem cells from mouse brains, from human-fetal brains, and from human embryos proved equally adept at battling the mouse version of Sandhoff disease. In people, that congenital enzyme deficiency is similar to Tay-Sachs disease and causes severe mental retardation and early death.

Evan Y. Snyder, who led the work at the Burnham Institute for Medical Research in La Jolla, Calif., says that the implanted cells knew exactly how to repair the brain: "Even the dumbest stem cell is smarter than the smartest neurobiologist."

The stem cells created all the major brain-cell types, including active neurons and support cells called astroglia and oligodendrocytes, Snyder's team reports online in Nature Medicine.

This "milieu" restored enzyme production and reduced brain inflammation, a hallmark of many neurodegenerative diseases, says Snyder. "We saw a series of actions that try to return [the brain] to baseline."

Dennis Steindler of the University of Florida, Gainesville, says that Snyder is at the forefront of a movement that champions stem cells as "little molecular factories" that might repair and protect brain tissue, not just replace damaged neurons.

Sandhoff disease springs from the lack of the enzyme hexosaminidase (hex), which dears excess lipids from the brain. In the absence of hex, damaging lipids accumulate. Children with Sandhoff disease rarely live past age 6. Some 50 other diseases, including Tay-Sachs, result from similar genetic deficiencies in lipid metabolism. These lysosomal-storage diseases, as they're called, affect about 1 in 5,000 people in the United States.

Mice in the experiment lacked the gene for hex. But the donor cells, implanted at birth, spawned new generations of cells that produced enough hex to enable the host cells to clear lipids. That delayed disease onset and extended life by 70 percent over that of mutant mice not getting the implants.

In the brain areas where the most stem cells settled, the researchers measured hex concentrations at 28 percent of those seen in normal mice. Roughly the same amount of hex appeared, regardless of the implanted cells' origins--whether mouse brains, human-fetal brains, or colonies of human-embryonic stem cells that had been coaxed to grow into neural stem cells.

"The good news was they performed almost identically," says Snyder. With fetal-brain cells, "nature's done the work" of making the cells specialize while in neural cells grown from embryonic stem cells, "the experimenter has done it." However, the cells of embryonic origin were easier to grow in the lab prior to transplantation.

In a new series of experiments, Snyder's group is implanting a second dose of stem cells in mice that had been treated at birth but in which Sandhoff-like symptoms nevertheless had appeared. "This is how I would do it in patients," he says.

The Burnham Institute plans to ask the Food and Drug Administration for permission to conduct a human trial of neural stem cells collected from fetal brains, says Snyder. Stem Cells Inc. of Palo Alto, Calif. is already testing the safety of such cells in children with Batten disease, another lysosomal-storage syndrome.