Stem Cell Researchers Take on Parkinson's

Parkinson's disease could be the perfect target for stem cell therapy. The etiology of this progressively debilitating disease is clear: scientists know what cells are affected, where those cells reside, when those cells are created during development, and what their target is. This information is reported in scores of articles on cell transplantation that use fetal cells to treat Parkinson's in animal models and people. The good news continues. New research shows that by using stem cells, scientists can produce an unlimited supply of dopamine (DA) neurons,1,2 the same neurons that inexplicably die off in Parkinson's patients. (Dopamine is the chemical that helps direct muscle activity.) Scientists at Rockefeller University and Memorial Sloan-Kettering Cancer Center recently reported that they produced DA neurons from adult somatic cells using "Dolly-esque" cloning technology.3 This finding raises the possibility that one day, therapeutic cloning could help generate DA neurons from a patient's own tissue, eliminating the worry that the tissue will be rejected and freeing transplant patients from having to take powerful immunosuppressive drugs. Now the down side: Numerous issues jeopardize continued stem cell research. The current political posture regarding research on embryonic stem cells, a troublesome and well-publicized clinical trial that has caused some to question whether cell therapy should even be done with people, and lots of unknowns about stem cell biology have made researchers cautious in predicting how quickly this field will progress. Assessing the situation, Donato Di Monte, director of basic research at the Parkinson's Institute, says, "There's no doubt in my mind that these are revolutionary and potentially important new techniques in Parkinson's disease, neurodegenerative disorders, and medicine. But we have to admit that we are not there yet, in terms of the applications of these techniques directly to patients." So far, several hundred Parkinson's patients and thousands of animals have received tissue transplants; but with people, only fetal cells have been used because stem cell research is still in its infancy. The question is: Will that research continue. Courtesy of Lorenz Studer.Confocal picture of dopaminergic neurons (green) generated in vitro from proliferating brain stem cells, as evidenced by BrdU incorporation. The Bush administration appears poised to reverse its predecessor's guidelines, which would have permitted federal funding of certain kinds of fetal cell research. On May 4, U.S. District Court Judge Royce C. Lamberth ordered a halt to any federally funded embryonic stem cell research, pending a Department of Health and Human Services review on the National Institutes of Health guidelines. [See main story.] Without federal funding, the high-quality studies needed to proceed will simply not get done, says Curt Freed, professor of clinical pharmacology and toxicology at the University of Colorado Health Sciences Center. He is the principal investigator on one of only two NIH-funded placebo-controlled clinical studies done in this country to date. Not helping with this scenario is the recent press maelstrom that followed the publicized results of Freed's clinical trial. The study, appearing last February in The New England Journal of Medicine,4 was unimpressive, as predicted by several researchers in the field,5 based on the region of the brain that received the transplant and the metric used to monitor its effect. A New York Times story written by science writer Gina Kolata, and subsequently picked up by numerous press outlets, presented a nightmarish view of the outcome. It emphasized some movement problems (dyskinesias) that a few transplant recipients experienced. The fear, say several scientists, is that the attention being paid to this trial will taint an otherwise promising field. Kolata told The Scientist that she stands by her story. For his part, Freed claims the results were positive and just as he expected, a view shared by the Nature Medicine editors, who wrote that "the small improvements achieved ... are remarkable and should encourage further research."6 Freed's results illustrate the need for more carefully controlled studies, but opponents of embryonic stem cell research will likely use them to argue that they should be stopped. Di Monte says, "It was a very tragic outcome, but it would be even more tragic if we don't take this opportunity to learn something out of this experience." Notwithstanding this recent setback, work with human fetal tissue has "blazed the trail for stem cell research in this field," according to Harvard University neurologist Evan Snyder. Through this work, researchers have learned the best way to do a transplant, what the pitfalls are, and how to approach it safely.7-9 Fetal cell implants are still "the gold standard," Snyder says, but "it takes many fetuses, and there's no guarantee that they'll be available in the quantities needed." To be sure, researchers are having a difficult time finding fetal cells because there isn't enough material from aborted and largely destroyed fetuses. Enter Stem Cells Neural stem cells, in addition to being more available than fetal cells, have other theoretical advantages over their controversial counterparts, according to Gene Redmond, director of the Yale Neural Transplant Program. Stem cells potentially could do more than replace lost dopaminergic neurons, as they can migrate throughout the brain and differentiate into other, supportive cells. In addition, they could be engineered to make factors that might rescue host cells or ensure their long-term survival. Work with stem cells and various animal models of Parkinson's disease has progressed along several lines, each with some success. Snyder created permanent neural stem cell lines from mouse neonatal cerebellum and from the forebrain of mid-gestation human fetuses.10 This, he says, was everyone's goal--"to go to the well once, pull out stem cells, and have stable, common lines." Snyder and his collaborators are transplanting these undifferentiated stem cells into a rodent model of Parkinson's disease, leaving the business of molding the cell's character up to the host tissue. In preliminary experiments in Snyder's lab, husband and wife team Vaclav and Jitka Ourednik have seen dramatic reconstitution of the substantia nigra in a rodent model of Parkinson's disease, as well as evidence that the transplanted cells can not only repopulate the DA-neurons, but can provide support for the host's own cells. To date, Redmond has developed what may be the most authentic animal model for Parkinson's using the neurotoxin MPTP (91-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine). The neurotoxin produces a Parkinson's-like paralysis in people, which was first discovered when so-called frozen addicts, high on tainted synthetic heroin, showed up in hospital emergency rooms unable to walk or talk.11 Redmond can induce a disease in African green monkeys that reproduces all the main signs and symptoms of Parkinson's. The model has been used extensively to study fetal cell replacement therapy, and will likely be a good predictor of whether stem cells will work in patients, according to Redmond. Development in a Dish Others are using "pre-differentiated" cells--stem cells that have been partially or completely coaxed into being DA neurons. Lorenz Studer, head of stem cell and tumor biology at Memorial Sloan-Kettering Cancer Center, can, by step-wise addition of specific proteins or growth factors, re-create brain development in vitro. After inducing embryonic stem cells to form embryoid bodies, he selects and expands neural cells. At this stage, the cells are susceptible to patterning cues and can be turned into the forebrain or midbrain, or by turning on the transcription factor gene, sonic hedgehog and several other genes, into DA neurons. Studer's not ready, though, to start transplanting his embryonic, stem cell derived, DA neurons into patients because safety and functionality issues remain. Although he can convert nearly all the cells into some kind of brain cells, purity is still a problem. The best he has done so far is 60 percent purity. Studer explains, "You would want to be sure that your cells are 100 percent free of non-brain cells, as there could be a few persisting embryonic stem cells that could turn into other tissues such as muscle or bone." While he sees this as a major concern, Studer points out that many strategies exist that can resolve the purity issue. Challenges Lie Ahead The list of what researchers still need to know about human stem cell transplants is long and challenging. According to Snyder, researchers are looking for "the best cell prep, the best place to put it, the best patients to get [the transplant]," and the safest way to expand neural stem cells. Careful, selective genetic manipulations could turn out to be more reliable than applying growth factors, which could have unwanted or uncontrollable effects, he says. Snyder says he doesn't believe the research itself will suffer because of politics. "Ultimately, the science itself will be so compelling that government won't intercede. And if [it does], there are private sources that researchers could turn to and circumvent any government-imposed restrictions. But here, the government loses out, as the technology becomes proprietary and commercialized, and the public loses out since the data won't be available for public scrutiny." Laura DeFrancesco can be contacted at defrancesco1@earthlink.net. References 1. J. Wagner et al., Induction of midbrain dopaminerginc phenotype in Nurr1- overexpressing neural stem cells by type I astrocytes," Nature Biotechnology 17:653-9, 1999. 2. S. Lee et al., "Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells," Nature Biotechnology, 18:675-9, 2000. 3. T. Wakayama et al., "Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer," Science, 292:740-3, 2001. 4. C.R. Freed et al., "Transplantation of embryonic dopamine neurons for severe Parkinson's disease," New England Journal of Medicine (NEJM), 344:710-9, March 8, 2001. 5. J. Cohen, "New fight over fetal tissue grafts," Science, 263:600-1, 1994. 6. Anonymous, "Prospects for Parkinson disease," Nature Medicine, 7:381, April 2001. 7. C.W. Olanow et al., "Fetal nigral transplantation as a therapy for Parkinson's disease," Trends in Neuroscience, 19:102-9, 1996. 8 O. Lindvall, "Cerebral implantation in movement disorders: State of the art," Movement Disorders, 14:201-5, 1999. 9. T.B. Freeman et al., "Use of placebo surgery in controlled trials of cellular-based therapy for Parkinson's disease, NEJM, 341: 988-92, 1999. 10 J.D. Flax et al., "Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes," Nature Biotechnology, 16:1033-9, 1998. 11 C. Gan, "How MPTP revitalized Parkinson's research," The Scientist, 2[23]:13, Dec. 12, 1988.

Stem Cell Researchers Take on Parkinson's

Interested in reading more?

Become a Member of