Investigational treatment for Parkinson’s disease in which neurosurgeons implant embryonic or adult stem cells into the pallidus or putamen. The procedure also is called stem cell transplant or stem cell therapy. The pallidus and putamen are structures of the basal ganglia that are instrumental to voluntary movement. The stem cells implanted into these areas have already been manipulated to differentiate as dopaminergic neurons and “take root” in the recipient brain. Once well established they produce dopamine just as do native dopaminergic neurons, boosting the brain’s supply of endogenous dopamine. This process seems to offset, but does not entirely compensate for, the loss of dopaminergic neurons from the substantia nigra. It is this loss, and the resulting depletion of dopamine, that cause the symptoms of Parkinson’s.
Although it would seem reasonable to implant dopaminergic stem cells into the substantia nigra, where they could directly replace dying neurons, researchers have chosen the putamen and pallidus as the recipient sites for stem cell implantation instead, in part because these structures are in close proximity to other structures of the basal ganglia and brain that are involved with movement and have abnormal activity in Parkinson’s. Neurons originating in the substantia nigra have long den-drite structures that allow them to extend to other structures; implanted cells here would have to be directed to grow these long dendrites as well, which is a difficult proposition. As well, because scientists do not know what causes the substantia nigra’s native dopaminergic neurons to die, reseed-ing the area with new dopaminergic neurons would make little sense.
Results and Effectiveness
The results of investigational stem cell implants for Parkinson’s are mixed. Some people who volunteered to participate in stem cell implant studies experienced immediate and dramatic relief of symptoms such as tremors and bradykinesia after implant and were able to reduce significantly the amount of levodopa and other anti-parkinson’s medications they were using, although they could not stop taking them entirely. The rate of positive responders has been much higher in open-label trials than in randomized-controlled trials, suggesting a significant placebo effect. Functional imaging studies in some of the open label trials have confirmed this placebo effect: Many of the patients with an apparent benefit did not have surviving grafts; the implanted cells died and did not form functional connections. In a randomized-controlled trial, only the youngest patients (those under 60) seemed to have had much of a chance of benefit. Other people noticed no appreciable difference in the severity of their symptoms. And still others found that their symptoms worsened, or they developed additional dyskinesias and dysto-nia because the implanted cells produced too much dopamine; 15 percent of those in the randomized-controlled trial had uncontrollable dyskinesias, even off of all medications. Based upon these results, much of the enthusiasm to conduct human clinical trials with current implantation techniques has waned, with scientists wanting to wait until better techniques, offering a better success rate and less risk of uncontrollable dyskinesias, have been developed.
Because stem cell implant is a relatively new therapeutic approach, scientists do not know how long the effects last or what long-term complications may occur. They do know that the degeneration of dopaminergic neurons continues in the substantia nigra, and the Parkinson’s continues to progress. However, the implanted dopaminergic neurons appear capable of sustaining a steady pace of dopamine production in a few people who have received stem cell implants.
Risks and Challenges
There are a number of risks inherent in stem cell implant. One is the transfer of disease to the recipient. Stem cells are taken from other humans, and therefore have the potential to pose a wide range of risks from genetic mutations to infections. Indeed, the risk of infection is itself a potential problem, as stem cell implant requires entering the inner portions of the brain. There is a risk of infection, as well as bleeding, in any kind of surgery. Another risk is the potential for the stem cells to differentiate into cells other than those intended, causing abnormal tissue growth or tumors, even cancerous lesions. Although research centers screen for as many potential problems as possible, this is a very new technology and there just is not enough information about what those possibilities may encompass. Once a stem cell implant takes place, however, its results, good and bad, are permanent. Implanted stem cells cannot be withdrawn or inactivated.
Other challenges confronting this technology are ethical and practical. Embryonic stem cell implants have polarized the research community, people with Parkinson’s, and the general public because these cells are harvested from human embryos whose development is arrested to provide them or from embryos that have been aborted. Because even one embryo can provide a virtually endless supply of stem cells, this is a highly controversial topic that has engendered intense debate and resulted in strict federal limitations on embryonic stem cell supplies and research.
Adult stem cell implant is not so controversial, as scientists can harvest adult stem cells without taking or risking the life of the donor. However, adult stem cells exist in limited quantities, are difficult to identify and harvest, and are difficult to cultivate and maintain in the laboratory. As well, most adult stem cells are unipotent: They have the ability to differentiate into cells of the tissue type from which they originate. Adult stem cells found in the brain so far have not demonstrated an ability to differentiate into dopaminergic neurons; research in this area continues.
On either front, stem cell implant is an expensive, high-risk procedure that, at present, offers unpredictable long-term benefits for people with Parkinson’s. There are many questions for researchers to answer before this becomes a viable treatment alternative.