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Saturday, December 16, 2006 Searching for a Cure for Parkinson's Disease With a heightened interest in Parkinson's disease (PD) a new optimism is emerging. Some scientists are predicting that if research into this disease continues at its present rate, PD may be preventable in the early 21st century. Let us hope they are right. The discovery of growth factors, new genes, stem cells, and new surgical techniques, just to name a few, all hold promise. But defeating PD will most surely require new discoveries that no one can yet predict. A "cure" for PD may come from an area of science that we never even suspected. Major discoveries are sometimes serendipitous. So when we speak of a cure, what do we mean? A treatment that slows or stops the disease progression, or ideally a treatment that relieves all major symptoms permanently and without risk of significant side effects. The following is an up-to-date review of those areas of research that show the most promise, to include a disappointment or two. * Neuroimmunophilins-Ligands * Neurotrophic Factors * Neural Tissue Transplants * Retinal Cell Transplants * Stem Cell Transplants * Gene Engineering and Therapy Neuroimmunohilins-Ligands In my opinion, this is the most promising discovery so far as a potential cure for PD. Let me give you a brief review of how these compounds were discovered and how they appear to work. The drug that started all this was FK-506, now known as Cyclosporin, an immuno-suppressant used to prevent rejection of organ transplants. It is also the first drug discovered that showed, in the test tube and in tissue cultures, that it could stimulate the growth of brain cells and help partially rejuvenate nerves. Because cyclosporin is a powerful immuno-suppressant with troublesome side effects, scientists had to try and isolate just the portion of the drug that was beneficial to the neurons and nerves. They were indeed able to isolate drug-like molecules called GPI-1046 or ligands that had the desired properties and not the unwanted ones. When given to animals with PD-like induced symptoms they were found to stimulate the regrowth of damaged neurons and eliminate all signs of PD. Another important feature is that these ligands can be given by mouth and cross the blood-brain barrier. A series of these ligands have now been synthesized. They bind to cellular proteins known as immunophilins, which are receptors on the cell surface that turn on repair genes within damaged nerve cells. This growth factor, GPI-1046, when given to Rhesus monkeys with MPTP-induced PD, resulted in a dramatic improvement in symptoms. Monkeys with difficulty walking, climbing and feeding themselves regained these abilities. The brains of these monkeys, under the microscope, showed evidence of re-growth of dopamine nerve terminals. So far in animal studies no toxicity or side effects have been observed. These drugs can regenerate damaged nerves with out affecting normal, healthy neurons. In summary, these drugs work by regenerating damaged neurons, resulting in a 90 percent recovery of normal behavior in animal trials. The scientists hope to be able to reverse PD in humans, which is unprecedented. Just think, an orally active molecule that crosses the blood-brain barrier and puts PD patients back to normal function. While this sounds like a potential cure, we await the results of clinical trials that may take a few years to complete. Neurotrophic Factors A substance called glial-derived neurotrophic factor (GDNF) was discovered in 1993. It was shown to promote the survival of neurons. What more do we know about this substance? All cells, including nerve cells, self-destruct when they are no longer needed. This type of suicide cell death called apoptosis is, in the brain, under the control of a genetic program that is permanently "on." Unless these suicidal cells are given the message not to, they will self-destruct. In the brain, the survival signals that save these cells are called neurotrophic growth factors. It was first thought that these neurotrophic factors were only involved in early brain development, but it has been shown that they are also involved in the survival of adult neurons. This raised the obvious question, could neurotrophic factors help PD? Further studies have shown that this factor appears to not only slow down the loss of nerve cells, but to prevent further neuron cell suicide. This could result in a treatment that could slow or prevent the further march of PD in the patient. Using a recombinant form of GDNF, Amgen has demonstrated in its laboratories, that r-metHuGDNF, which has to be injected into the brain, works to protect dopaminergic neurons against chemical insult and can ameliorate PD symptoms in chemically lesioned animals. The r-metHuGDNF has been injected into brains of Rhesus monkeys with MPTP-induced PD; significant improvement occurred in these primates with a marked reduction in slow movement, rigidity and postural instability. All the results indicate that GDNF may be of benefit in treating humans with PD. Perhaps this treatment's main drawback is that this molecule cannot be given by mouth, or injected into the blood stream, nor does it cross the blood-brain barrier. It must be injected, once a month, directly into the brain through a surgically placed catheter. This study is ongoing at multiple PD centers in North America. Neural Tissue Transplants In the 1980s, neurosurgeons in Sweden and China transplanted tiny bits of aborted fetal brain tissue into the brains of patients with PD. The idea was that if these cells "took" the PD patient would be able to produce more dopamine. However, success of this procedure has been slow in coming, hampered by ethical and moral issues; the controversy is over the use of human fetal tissue for the implants. A Federal ban, lifted in 1993, will probably resume under the new US administration. If this happens, funds for this research may no longer be available from government agencies. Results released this year from the first randomized, controlled clinical study of fetal implants for PD patients show that the surgery only helped a small number of patients under age 60. This was a study led by Dr. Curt Freed from the University of Colorado in Denver and Dr. Stanley Fahn of the Columbia-Presbyterian Medical Center in New York. Their study included 40 patients with advanced PD present for an average of 14 years. After one year the treated patients under age 60(nine in total) showed some improvement especially in movement. However, no patient over age 60 or the placebo group showed improvement. The most shocking finding was that in 15 percent of patients, the cells grew too well resulting in too much dopamine produced in the transplant patient's brain. As a side effect, these patients developed uncontrollable writhing and jerking movements, known as diskinesias with a severity rarely seen. The scientists say they have no way to remove or deactivate these transplanted cells so this nightmarish side effect may be permanent. Although some scientists are eager to proceed, the results of this study, plus the dispute over ethical issues surrounding it may mean that the grafting of human fetal tissue into the human brain may no longer be considered a safe, viable option for treating PD. Retinal Cell Transplants Scientists from Emory University in Atlanta have recently reported on a new approach to the transplantation of dopamine producing cells that does not rely on controversial human fetal cells. Instead it uses what are known as retinal pigment epithelial cells, a readily available source of dopamine producing cells found in the retina of the eye. Why these cells are there and their function is unknown, but they appear to be effective when used in human brain transplantation. The cells can be obtained from donor eyes at organ banks grown and multiplied in the laboratory. For brain implantation the retinal cells are deposited on the surface of tiny gelatin spheres barely visible to the naked eye. Hundreds to thousands of these spheres, called Speramines, are injected into the brain. One donor eye can potentially provide enough cells to perform thousands of transplant operations on PD patients. Unlike fetal cells, immune cells in the brain do not attack these retina-derived cells, which is a significant finding. At Emory six patients with moderate to severe PD underwent the transplantation. Within the first three months of the treatment all six patients showed a 35 percent improvement in their symptoms. Some were even able to reduce their medications. The results are encouraging, but because this was not a placebo-type study, the results are open to question. Controlled clinical trials are needed before any conclusions can be drawn. Stem Cell Transplantation The discovery of stem cells in 1998 has refocused attention to brain repair. Stem cells are the universal cells from which all cells are derived. They can be grown in test tubes and made to specialize into any type of cell, including neurons. (Theoretically, if this is proven to be true, PD patients would get an injection of these newly produced stem cell-derived neurons into the substantia nigra and be cured.) That sounds too good to be true and considerable work needs to be done. There is also the issue of ethics as these stem cells come from human fetal sources. At present the current use of human pluripotential stem cells is under discussion and remains an unresolved ethical controversy. But scientists are resourceful. A recent study found that bone marrow cells could be induced to develop into brain cells. This gives scientists a safe, reliable uncontroversial source for stem cells. A recent report in the April 2001 issue of Tissue Engineering found adult stem cells in the human fat from liposuction patients. The next step is to test if these cells will transplant successfully, transform into the right kind of cell, and prove to be as good as cells taken from a human fetus. Scientists at Lund University, in Sweden, have reported that human neural stem cells grown in the laboratory can be used to generate new neurons in the brain. The main limitations are safety and ethical issues. Alternative sources like bone marrow are needed. Many are convinced, however, that in a matter of years it will be possible to use stem cells to repair damaged tissues and organs including the brain. This sounds like a potential cure for PD. Gene Engineering and Therapy I have alluded to genetic engineering whereby scientists modify the genetic code of individual cells to create dopamine-producing cells from other cells, even skin cells. The implications for PD are obvious. The other important area is gene therapy. The recent FDA approval of the first commercial use of gene therapy can open new ways in which this therapy can supply PD patients with the neurotransmitters they lack. People with hereditary diseases cannot make a certain protein because the gene that codes it is damaged or missing. Gene therapy then is the implant of the normal gene into the body so that the normal protein will be generated. Although gene therapy sounds easy on paper, it is actually a difficult and complex procedure that must be methodically done. The main concern is safety. In present techniques a disabled virus is used to introduce genes into cells. The risk is that the viral vector might trigger the wrong genes in the persons DNA or become active. The other main concern is possible severe side effects from the procedure that may be life threatening. Researchers from the Research Center for Brain Repair at the Rush Presbyterian St. Luke's Medical Center, Chicago, used monkeys experimentally induced with PD for a recent gene therapy study. The experiment relieved the severe symptoms of PD and restored them to normal. Posted by ushakanth at 12:59 AM ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn