Stem cells transplanted into animals' brains for Parkinson's study
BY JOHN FAUBER AND SUSANNE RUST
Milwaukee Journal Sentinel MILWAUKEE -
Human stem cells genetically engineered to produce a substance that might protect the brains of Parkinson's patients were successfully transplanted into the brains of monkeys and rats by University of Wisconsin-Madison scientists, a feat that represents a crucial step in developing a promising treatment for the disease.
The transplanted cells appeared to do what they were designed to do: They migrated to a target location in the brain, pumped out the substance and helped the animals' brain cells survive and sprout new fibers.
However, as often is the case with stem cell research, the experiment also migrated into the murky world of biomedical ethics.
By transplanting human cells into animals, the researchers created chimeras, creatures that contain cells of two different species.
It was the second time this week that researchers reported they had created human/animal chimeric brains.
Earlier this week, researchers from California reported that they had injected human embryonic stem cells into the brains of embryonic mice. Again, the cells not only survived, but also migrated into different areas of the developing brain and became several kinds of neural cells.
Although both experiments involved chimeric animals, their bioethical considerations are different, according to Norman Fost, a biomedical ethicist at UW-Madison.
The concern about putting human stem cells into animal brains is that you could create a situation that Fost calls the "help, let me out of here scenario," in which human cortical tissue is created in the skull of an animal, potentially creating a human-thinking being in a non-human body.
In the UW paper, which appears Thursday in the journal Gene Therapy, the concern for this happening is negligible, Fost said. The cells were injected into adult animal brains.
For their study, the UW researchers did not use embryonic stem cells. They used neural stem cells derived from aborted fetuses obtained from a fetal tissue bank in Seattle.
The cells then were infected by an inactivated virus that was genetically engineered to produce a substance known as glial cell line-derived neurotrophic factor, or GDNF.
Neurotrophic factors, also known as growth factors, are a family of proteins that nourish brain cells, helping them develop and maintain function. They also may be able to repair damaged brain cells and regenerate new ones.
Short of a cure, it is hoped that these proteins someday may buy time for patients with diseases such as Parkinson's, amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, and even Alzheimer's - more than now is offered by the best available medicines and possibly enough to keep the diseases at bay for years.
In animals and some preliminary human studies, GDNF has been found to improve symptoms of Parkinson's disease.
Citing safety concerns, Amgen Inc. announced earlier this year that it had stopped supplying GDNF for early clinical trials involving 48 Parkinson's patients who had been getting the drug pumped directly into their brains via a catheter.
However, several of the patients who say they got substantially better have pleaded with the company to resume supplying GDNF, so far to no avail.
Rather than using pumps and catheters, the UW researchers injected their engineered cells directly into the brains of seven rats and three rhesus monkeys.
The cells not only survived for up to three months, but also were releasing significant amounts of GDNF, which led to improved survival of brain cells that made dopamine and growth of new cell fibers. Parkinson's is a disease of brain cells that make dopamine, a brain chemical that regulates movement.
The rats in the study also appeared to have improved function.
By injecting drug-making cells directly into the brain, scientists can avoid problems caused by the blood-brain barrier, a layer of protective cells that keeps many toxins - and many beneficial drugs - out of the brain.
"The beauty of this is you can use the stem cells as the Trojan horse," said Clive Svendsen, a UW neuroscientist and senior author of the paper. "And once you put them in the brain, they make it (GDNF) for free."
In addition, Svendsen said he believes he has a viable method for turning the cells on and off by using a common antibiotic, even though that technique did not work in his most recent study.
Using fetal tissue cells also gets around a lingering concern about embryonic stem cells: their potential for causing tumors.
However, the downside to using fetal cells is that such an approach most likely will require the use of potent anti-rejection drugs.
The UW paper is an important step in a potential therapy that likely will be tried in Parkinson's and ALS patients within the next five years, maybe sooner, said Theo Palmer, an assistant professor of neuroscience at Stanford University School of Medicine.
"It's the first milestone," said Palmer, who was not involved with the study but who is collaborating with Svendsen on other research.
The study's findings are fascinating and the approach clearly shows promise, said Bradley Hiner, an assistant professor of neurology at the Medical College of Wisconsin who treats Parkinson's patients at Froedtert Memorial Lutheran Hospital.
However, it is a disservice to Parkinson's patients to call it a potential new treatment. Doing so gets their hopes up when clinical trials likely are years away, he said.
"It's a little premature to think about this as a potential treatment for humans when only three primates were done and the results were equivocal at best," Hiner said. "There's obviously quite a bit of work before anyone is getting this transplanted into humans."
And while Fost, the UW bioethicist, didn't comment on the ramifications of the study, he did say that it was clean from an ethical standpoint. Although he said the aesthetics of the work - putting human brain cells into the brains of animals - might strike some as repugnant.
"But the `yuck factor' isn't an ethical consideration," Fost said. |
