President Franklin D. Roosevelt admonished in a 1932 commencement address that “it is common sense to take a method and try it. If it fails, admit it frankly and try another.” FDR had the revival of a depressed U.S. economy in mind, but scientists experimenting with treating brain disorders with fetal cell transplants have taken his aphorism to heart. New methods are transforming past failures, and the results seem far more promising this go-round.
Fetal cell therapy began in earnest in the mid-1980s, among researchers hoping to treat Parkinson’s disease. These patients have trouble controlling their movements partly because their brains lack the neurotransmitter dopamine. The hope was that tissue from fetal midbrains placed into patients’ brains would turn into dopamine-making cells. Shortly after the turn of the century, however, the work foundered when a subset of transplant patients developed disabling movement disorders termed runaway dyskinesias.
But amid the setbacks was the fact that some subjects—especially those who were younger and less afflicted—did well with the fetal cells. “The question is, How do we reconcile all these disparate strands and problems with these trials and move the field forward?” says Roger Barker, a neurologist at the University of Cambridge who is meta-analyzing prior transplant data in hopes of devising a better trial. One possible explanation for the mixed findings is contamination: transplant tissue containing serotonin-secreting neurons could have muddied the results.
Although fetal cells may need support from other, nearby cells in a tissue transplant, Barker concedes that the field is moving to transplanting pure stem cells, rather than tissue. He and others are particularly heartened by safety results last year of the first fetal neural stem cell trial approved by the U.S. Food and Drug Administration. The phase I trial enrolled children born with Batten disease, a fatal neurodegenerative illness in which genetic mutations render patients unable to produce enzymes needed to clear cellular waste.
In the trial, six children had up to one billion fetal neural stem cells injected into the ventricles of the brain or into white matter tracts. None exhibited ill effects, and an autopsy of one child who died from the natural course of the disease indicated that the transplanted cells had grafted nicely into the brain.
This result is a big advance in the field, says Robert Steiner of the Oregon Health and Science University who was a principal investigator on the trial. “This is a much more sophisticated approach to doing neural cell transplants by actually purifying and only using fetal neural cells rather than the mix of cells used in the earlier trials,” he notes.
Achieving high degrees of purity—that is, assuring that the vast majority of cells being transplanted are only neural stem cells—requires careful separation of cells. StemCells in Palo Alto, Calif., which produced the cells for the trial, employed a technique that labels fetal neural stem cells with a fluorescent tag. That makes them easy to see and sort from other cells. With the technique, the firm says that at least 90 percent of their proprietary cells are neural stem cells—a critical benchmark for FDA approval in clinical trials.
The success of the safety trial has given the FDA confidence to green-light a second trial, this time for children with Pelizaeus-Merzbacher disease (PMD), a genetic disorder that compromises the creation of myelin, a fatty substance that sheaths the axons of nerves. The trial will inject neural stem cells into the brains of four children with PMD and use magnetic resonance imaging to track new myelin formation. Preclinical trials in animal models of PMD have demonstrated that the cells can differentiate into myelin-forming cells called oligodendrocytes and successfully create myelin sheaths, but they have yet to prove they can restore function.