Science 11 April 2008:
Signs of Disease in Fetal Transplants
In the 1990s, an experimental treatment for Parkinson's disease raised hopes that the devastating movement disorder might be on the verge of yielding to modern medicine. Doctors reported that by extracting dopamine-producing neurons from aborted fetuses and injecting them into the brain to replace neurons destroyed by the disease, they were able to restore some patients' mobility. But despite its early promise, the procedure has had a contentious history. From the start, abortion foes objected to using fetal tissue, and two high-profile clinical trials later found that the surgery offered little to no benefit and appeared to cause involuntary movements in some patients.
New studies add another wrinkle to this complex story, revealing that implants can survive a decade or more but in some cases appear to acquire signs of Parkinson's disease--a surprising finding that could shed light on the disease's mechanisms.
Sign of trouble? Clumps of -synuclein (brown) inside transplanted fetal neurons suggest that Parkinson's disease can spread from the host brain into younger cells with different genetics.
CREDIT: J.-Y. LI ET AL., NATURE MEDICINE (6 APRIL 2008)
Three independent research groups report online this week in Nature Medicine findings from postmortem examinations of a total of six brains from Parkinson's patients who received the fetal transplant surgery between 9 and 16 years earlier. They are the first postmortem studies done this long after the surgery. All three studies found that many transplanted cells--identified by their pigmentation and staining for an enzyme involved in dopamine production--were apparently alive and well-integrated in the patients' brains. But two of the teams--one led by neuroscientist Jeffrey Kordower at Rush University Medical Center in Chicago, Illinois, the other by Patrik Brundin at the Wallenberg Neuroscience Center in Lund, Sweden--found that a small proportion of the surviving cells showed a hallmark of Parkinson's pathology: clumps of protein containing -synuclein and ubiquitin. The third team, led by Ole Isacson at Harvard University, saw no signs of Parkinson's pathology in the transplanted cells in the brains they examined.
"I think it's extremely intriguing," says Stanley Fahn, a neurologist at Columbia University. The Brundin and Kordower groups' findings suggest that the disease can spread from the host brain to much younger neurons with different genetics, Fahn says. "We know that age is the most important risk factor for Parkinson's disease, but here these neurons are only 14 years old," he says. "It opens up the possibility of some new pathogenic mechanism we hadn't thought of before."
The reason for the discrepancy with Isacson's group's findings isn't clear, Fahn and others say. Differences in surgical techniques or differences in the patients' immune reactions to the transplanted fetal cells might be important factors, says D. Eugene Redmond, a veteran Parkinson's researcher at Yale University.
Researchers are divided about what bearing, if any, the findings have on expectations for future cell-transplant therapies, including possible stem cell treatments. "Personally, I think it's encouraging," says Redmond, who points out that all three studies documented long-term survival of transplanted neurons. "If you could provide a benefit, … even if it only lasts 10 or 12 years, I think most people would see that as a great improvement."
Fetal transplant surgery is rarely done now, but some researchers, including Brundin and Isacson, still think the method holds promise and can be improved. A consortium of North American and European researchers is planning a clinical trial to see if the surgery offers consistent benefits and to help pave the way for stem cell transplants, should they become available.