Fetal Pig Neural Cells for Parkinson Disease

Seattle Studies in the last decade have suggested that transplantation of human fetal brain tissue is effective in slowing progression of Parkinson disease (PD) in some patients. However, the limited supply of tissue—not to mention the moral objections and ethical questions raised by its use—have generated interest in finding alternative, nonhuman species to use for such transplants.

One promising source of fetal brain tissue is the pig. Among the benefits of using porcine cells are pigs' large litter size (10 to 15 fetuses) and short gestation period, said Samuel A. Ellias, MD, PhD, of Boston University Medical Center, at a conference on the Etiology, Pathogenesis, and Treatment of Parkinson Disease and Other Movement Disorders held here in October.

Twelve million fetal porcine ventral mesenphalic cells were divided into three tracks and transplanted unilaterally into the caudate and putamen of 12 patients with Parkinson disease. (Photo credit: Jill Ghormley)

But among the concerns raised by xenotransplantation, Ellias reminded listeners, is cross-species infection (JAMA. 1995:274;285–288). Although most potential pathogens can be eliminated from fetal pigs before transplantation, Ellias said it is important when using porcine tissue in transplantation to test for porcine endogenous retrovirus (PoERV), which is resistant to eradication because it permanently integrates into the pig genome. Therefore, further animal and clinical research is needed before brain grafting with fetal pig cells can be contemplated as a treatment for PD.

SAFETY AND EFFICACY

Ellias and his colleagues have been evaluating the safety and efficacy of using fetal pig brain tissue transplantation. Results from a phase 1 study sponsored by Diacrin Inc and Genzyme Tissue showed a favorable safety profile and provided preliminary evidence of efficacy of this approach, he said.

The average age of the 12 patients in the study was 60.8 years, with a range of 37 to 70 years. All patients had moderate to severe PD, with the mean Hoehn-Yahr stage (a 1-to-5 staging scale for PD) being 3.7 OFF. All of the patients had had the disease for about 14 years, and in none of them was medication useful in alleviating symptoms.

The patients received unilateral transplantation of porcine ventral mesencephalic cells from day 25 to 28, with a total of 12 million cells being distributed in three tracks—one in the caudate and two in the putamen—with 4 million cells per track. After surgery they were randomized into two groups, with one group of six patients receiving cyclosporine and the other group of 6 treated with an F(ab'2) antibody fragment directed against major histocompatibility complex (MHC) class 1.

The patients' ability to perform a variety of movements was assessed postoperatively every 3 months for 2 years using a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Of the 12 patients, two patients, both in the group receiving cyclosporine, were not fully evaluable over the full duration of the study, said Ellias. One was excluded from the group analysis because his condition was so poor at the time of baseline testing that all measurements could not be taken. Ellias noted however that after surgery this patient has shown remarkable improvement. The other patient died 7 months after transplantation from a pulmonary embolism, a cause believed to be unrelated to the treatment.

A member of the audience remarked that a small number of other transplant recipients had also succumbed to pulmonary emboli, raising the issue of whether there might be a causal relationship. In spite of the fact that pulmonary emboli are more likely to occur in these patients simply because of their age, Ellias said he has had similar concerns about a possible connection and thinks it should be investigated.

FAVORABLE RESULTS

Ellias said no serious adverse effects were noted that were directly related to the porcine cells, and safety testing for PoERV with a polymerase chain reaction–based assay detected no sequences of the virus. He added that further evidence for the safety of using this material in humans appeared in an article published in August on the longitudinal expression of PoERV in humans who have been exposed to living porcine tissue (Science. 1999:285;1236-1241).

In addition, Ellias said no worsening of dyskinesia or dystonia was seen, no spontaneous dyskinesias developed, and a number of patients showed improvements in dyskinesia. At 2-year follow-up, an 18% improvement (P<.05) was seen in the total UPDRS (OFF) score, 22% for the group receiving cyclosporine and 15% for those receiving the antibody. Statistically significant improvement was gained from treatment in activities of daily living, postural instability, and complications of treatment.

One patient who had been in the cyclosporine group showed 45% improvement at 12 months and maintained this change at 24 months. A patient in the antibody group showed 51% improvement at 12 months, which was maintained through the next year. Both patients showed bilateral responses in arm speed and sustained improvement in walking speed, despite the fact that the graft was unilateral. Ellias said these results warrant further trials.

Eighteen volunteer patients have been enrolled in a double-blind controlled trial involving bilateral implantation of twice the number of fetal porcine brain cells used in the phase 1 study. Patients will be randomized into a group that receives the transplants and a control group that undergoes a surgical procedure but does not receive these cells. "We believe it's necessary to do this in a placebo/sham surgery trial to make sure some of these effects are not placebo effects," said Ellias. Results from this study should be in by next August, he said.


M. J. Friedrich
Vol. 282 No. 23,
December 15, 1999
Medical News & Perspectives
1999 American Medical Association. All rights reserved.

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janet paterson
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