When a person shows up in the doctor's office with stiff, rhythmic hand and limb tremulous movements, shuffling gait, droopy posture and masklike facial expressions, the physician diagnoses Parkinson's disease and routinely writes a prescription for L-dopa - levo-dopamine. This tried-and-true drug replaces the missing dopamine, the key neurotransmitter feature of PD, and corrects the familiar symptoms.
So far, so good - but far from enough. Dosing multidaily L-dopa tablets works well for some time but eventually wanes in efficacy. Instead, an even less bearable disorder called dyskinesia worsens the disease. Its uncontrollable movements can't be treated with standard medical therapies. In severe cases, the dyskinesia must be abated with brain surgery.
As far back as 1817, a British physician named James Parkinson (1755-1824) published his Essay on the Shaking Palsy. This moniker stuck until well in the 1800s when the celebrated French neurologist Jean Charcot renamed it "Parkinson's disease." It took until the mid-1960s for L-dopa to reach the neurologist's prescription pad. It was hailed as a wonder drug, allowing PD patients to leave their beds and lead seminormal lives. That euphoria lasted until the dyskinesias brought doctors and patients back to grim reality.
In November of 1988, neurologist Curt Freed at the University of Colorado performed the first fetal dopamine cell implant into an American PD patient. That attempt yielded controversial results, but the approach caught on. Seven years later, Freed could announce that he had transplanted human fetal tissue into the brains of another 17 patients. He observed that "fetal mesencephalic dopamine cells survive transplantation and relieve signs of advanced Parkinson's disease." In June 1995, Freed told BioWorld Today that because of the limited availability of fetal tissues from legal abortions, "the search for an unlimited number of cells for transplant would be a very desirable thing."
Pivotal Trial Spurns Fetal Cell Transplants
Now, the larger shoe has dropped. On Aug. 22, 2003, the Annals of Neurology released an online article titled "A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease." Its co-senior authors are neurosurgeon Thomas Freeman at the University of South Florida and neurologist Warren Olanow at Mount Sinai School of Medicine in New York.
Freeman is president of the American Society of Neural Transplantations and Repair. He also is medical director of the Center for Aging and Brain Repair at the University of South Florida, which performed all the surgeries in this clinical trial.
"In 1995," Freeman told BioWorld Today, "our group was the first autopsy study published in the world to demonstrate that neural grafts could survive in human brains.
"Precisely 56.5 percent of the PD patients in this clinical trial who received a fetal implant developed a new phenomenon that was observed in the Colorado study as well, where the patients suffered dyskinesias - abnormal movements - during their off time from medication. Normally, this is a sign of dopamine overdose. So the description in the off stage was attributed in the Freed study to too many dopamine cells being transplanted. We found the opposite to be the case. The dyskinesias were present in both the low doses and high doses to the transplant recipient. So this is not a dose phenomenon. As a matter of fact, we take it as the converse.
"Our next novel finding," Freeman continued, "is that this type of dyskinesia is seen when dopamine is wearing off from a low dose of L-dopa. It's called diphasic dykinesia. It's really a different type of dyskinesia than what you see with high-dose dopamine. So the interesting thing is that we can find graft survival in all the patients in this study as well as previous studies that proceed to autopsy. The next important point," he added, "is that we did have significant improvement in outpatients in all groups at six and nine months. The benefit disappeared at nine to 12 months.
"The dyskinesias also started in this same period," Freeman went on, and asked rhetorically, "Why then were we losing efficacy after we stopped the immunodepression treatment even though the cells were surviving at autopsy and at PET scan? Our hypothesis is that something was happening immunologically at the receptor level."
"First," Olanow observed in a press release, "we found that patients with mild disease were significantly improved with transplantation. Second, transplanted patients did improve until immunosuppression was stopped." But he summed up the trial's results: "With 50 percent of the patients transplanted developing dyskinesia, we cannot recommend this fetal transplantation as a therapy at this time."
Freeman noted that "we now have to go back to the laboratory to confirm our hunches in rats before recommending the next set of human trials."
Two Perspectives: Biotech, Pharmaceutical
"First," Freeman pointed out, "we absolutely must move away from fetal tissue and into the biotech domain - which means, making cells in vitro. The next interesting biotech issue is for a cell line not only to work clinically but to be manufactured in such a way that it can go into patients. It's necessary to find commercial partners. Large pharmaceutical corporations, to date, have unanimously shied away from partnering in these fetal technology platforms.
"Therefore, the platforms most likely to succeed, from the corporate perspective, are those that are nonfetal in origin. This includes proliferation of adult cells, adult stem cells and stem cells from umbilical cord blood. So from a biotechnology perspective, many scientific questions are likely to be answered using embryonic stem cells. But from the corporate perspective, if similar results can be obtained using nonfetal sources, these are more likely to be more acceptable for large pharma corporations willing to partner.
"Our results demonstrated," Freeman recounted, "that - unlike the Colorado study - age of PD onset was not the critical issue. Patients with earlier-stage disease tended to be big groups that had long-lasting improvements. And the final point is that this study validated the importance of using a placebo-controlled trial design for surgical intervention.
"There is a large trial ongoing internationally," he noted, "transplanting Spheramine - retinal pigment epithelial cells (from Titan Pharmaceuticals Inc.) - into the brain for PD. This trial is under way right now in Europe and America," he concluded.