Parkinson's disease is a debilitating neurodegenerative disorder that targets dopaminergic cells in an area of the brain called the substantia nigra. Most patients are treated with the drug Levodopa, a dopamine precursor that converts to dopamine in the body. Because the majority of damage occurs to a specific type of neuron in a tiny region of the brain, many researchers think stem cell transplants, or the replacement of the disease-ridden brain cells with healthy, dopamine-producing stem cells, might help ease symptoms like tremors and muscle rigidity-perhaps even better than existing drugs. Researchers from Harvard University-affiliated McLean Hospital have shown that one first step seems to work: Fetal dopamine cells transplanted into the brains of late stage Parkinson's patients remained functional for more than a decade after the procedure.
Ole Isacson, director of the Neuroregeneration Research Institute at McLean Hospital, was inspired to try fetal stem cell transplants in these people after observing successful transplants in rodent models of neurodegenerative disease.
"Many years ago, we learned that new cells put into old brains were able to connect up with the whole circuitry. We used primary fetal neurons from mice to do just that in mice and rats," he says. "We hypothesized this kind of treatment could also be restorative when cells die in the brain, like in cases of Parkinson's."
Over the past twenty years, Isacson and colleagues have treated approximately two dozen patients with their unique transplanting technique. In most cases, patients saw marked improvement in their physical symptoms. In fact, many patients were able to stop taking drugs like Levodopa altogether, says Ivar Mendez, a neurosurgeon at Canada's Queen Elizabeth II Health Sciences Center and the transplant surgeon.
"It was surprising. It was the whole idea-the new cells were able to replace the dopamine in the brain," he says. "But we didn't expect that it would work well enough that we'd be able to withdraw all the external dopamine."
Still, it was unclear how these improvements were occurring, or even if the transplanted cells could remain healthy over time. To examine these issues, Isacson and his team looked at the brains of five transplant patients who had died of causes other than their Parkinson's, focusing on the morphology of the transplanted cells. The group found that the transplanted fetal dopamine neurons remained functional, even after as long as 14 years, with healthy mitochondria (the cell's energy producing organelles) and dopamine transporters, proteins that help take dopamine back up out of the synapse after neurotransmission. The results were published in Cell Reports' June 5, 2014, issue.
"The transplanted cells connect and live well and do all the required functions of nerve cells for a very long time," says Isacson. "And what our progress heralds is that we don't always have to depend on drugs and chemicals to restore function. Rather, we can engage in methods that repair structures and restore function."
A promising technique
While Isacson's team has reported success in their patients, other stem cell transplant trials have had more mixed results. Mendez thinks the improvements seen in their patients is due, in part, to their surgical technique.
"First, we incubated the cells before transplanting them into a patient with a trophic factor [helper molecules that allow a neuron to develop and maintain connections with neighboring cells]. This enhances the survival ability of the fetal dopamine cells, giving them a boost before they are even transplanted," he says. "But we also used a small cannula [tube] for the transplantation itself that allows us to transplant the cells in a very precise manner with almost no trauma to the brain."
Using that cannula, Mendez injected the prepared fetal cells into four different areas of the brain. "For the cells to survive, they need to connect to the host brain so they can get nutrients," he says. "If you have one big conglomeration of cells, like some other transplants have done, it's harder for the cells to connect up. You would have cells in the middle of that conglomeration that would be too far away from the host tissue and those nutrients to survive."
Given the long-term health of the transplanted cells, both Isacson and Mendez are hopeful that this technique will one day be used for the transplantation of induced pluripotent stem cells (iPS). [See "New Cell 'Reprogramming' Techniques Could Hold Promise for Neurodegenerative Disorders"]
"iPS could be even better than fetal cells because we would be able to match them better immunologically to the patient," he says. "Since that method starts with the patient's blood or skin cells, we'd be able to match the transplanted tissue in an optimal way. The data support the development of cell therapies-it's a reasonable and rational thing to proceed with."
The future of stem cell therapies
Most proponents of stem cell transplants say that these therapies are still years away from regular clinical use. [See "Reprogramming Stem Cells Directly in the Brain"] Lawrence Goldstein, scientific director of the University of California San Diego Stem Cell Program, says Isacson's results are very encouraging-yet we need to proceed cautiously.
"Positive studies like this one raise hope that we can one day get this done. But it takes years to evaluate each experiment," he says. "We're now at a time where we are going to have to rely on brave human volunteers who will help test these new experimental treatments. It's the only way to discover what's really going on, and then decide what's the best path forward to get the best results."
He says that, both in Parkinson's disease and other neurodegenerative disorders that may benefit from stem cell transplants, we need more data to make sure they are as safe and an effective as current drug therapies.
"These things look very promising, I know," he says. "But we need to take the time and do the work-and that's going to take years so we can really track how these kinds of treatments change the rates of progression-so we make sure stem cell therapies work better than the alternatives."