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Institute of Medicine (US) Conference Committee on Fetal Research and Applications. Fetal Research and Applications: A Conference Summary. Washington (DC): National Academies Press (US); 1994.

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Fetal Research and Applications: A Conference Summary.

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Fetal Tissue Transplantation for Patients with Parkinson's Disease

RICHARD ROBBINS

Yale University School of Medicine, New Haven, Connecticut

Upwards of a million people in the United States have Parkinson's disease, a progressively degenerative condition affecting movement. The tremor and motor-control loss that characterize it result from the death of a group of brain cells that produce the neurotransmitter dopamine. What causes the cells to die—whether a virus, an environmental toxin, or another agent—is not known.

Therapy using L-dopa, the precursor of dopamine, alleviates the symptoms of parkinsonism for five to ten years, after which patients frequently develop resistance to it. Other approaches have been tried, including slow-release dopamine implants and transplants of the patient's own adrenal cells, which had to be stopped because of adverse side effects. Experimental work in this disease progressed slowly for decades, because there was no good animal model of the disease. That situation was changed almost 10 years ago by a tragic accident. An illegally produced "designer" drug containing a contaminant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was taken by a number of young healthy individuals, who then developed very severe parkinsonism. Once the cause was established and MPTP was shown to produce the same effect in animals, a badly needed animal model was suddenly available. The work of the Yale-Rochester private implantation group at St. Kitt's clearly demonstrated that fetal dopaminergic tissue could innervate MPTP-damaged brain regions and reverse the neurological defects. The idea of transplanting fetal dopaminergic cells into Parkinson's patients grew out of this work.

Thirteen Parkinson's patients have received fetal tissue transplants in Yale University's Neural Transplant Program. Because of the long-standing ban on federal funding of fetal tissue transplantation, the program has been privately funded. The tissue used in the program is collected from elective abortions. The women who consent to its donation are in no way influenced in their decision to terminate pregnancy; the request for donation is made only after the women have already signed consent forms for the abortion. The normal abortion procedure is also not changed in any way. Donors cannot specify who will receive the tissue, no money is exchanged, and no one involved profits financially.

The neurons in the donor tissue, usually from a seven- or eight-week fetus, are still immature, captured soon after they have committed to becoming dopaminergic cells, but before they have fully differentiated. The tissue is microdissected by a neuroanatomist into small blocks that contain supporting glial cells. These cells are believed to secrete growth factors important to the development and differentiation of dopamine neurons. Cryopreservation is used to store the tissue, because about six weeks of testing are needed to ensure that the tissue is free of infectious agents. The dopamine content of the cells is also evaluated. Storage also permits surgery to be scheduled at a time of optimal health of the patients.

When a patient is ready for surgery, an atlas of his or her brain is created by means of magnetic resonance imaging to ensure safety and accuracy in the placement of the implant. The procedure, which takes about six hours, is done under local anesthesia and the patient usually goes home the following day. All of the patients undergo intensive preoperative and follow-up neurological and psychological evaluation. Their status is tracked, along with that of a nonoperated control group, in a ''blind'' manner so that the examiners do not know which patient has received a transplant and which has not. Improvement in motor function generally begins several months after surgery and continues for up to two years.

Although not cured of their disease, these patients perform better than they did under optimal medication before implantation, and they perform still better if they have medication, in reduced dosages, after surgery.

Continuing research is directed toward questions such as the following that are critical to the progress of implantation therapy for Parkinson's disease:

  • What is the optimal age of fetal tissue for implantation?
  • How much of the tissue should be placed—and where?
  • What are the most sensitive noninvasive measurements of graft viability?
  • Which cells in the graft are responsible for improvement?
  • Should growth factors be added to the grafts?
  • How would graft rejection be detected?
  • How much immunosuppression should be used? For how long?
  • Are outcomes among transplant centers comparable?
  • Will there be enough fetal tissue for sufficient trials?
  • Should procedures to collect tissue be modified?
  • Should dopamine cells be genetically engineered for controlled proliferation?

Dopamine neurons arise in a part of the midbrain called the substantia nigra and communicate with the striatum, further forward in the brain, specifically with the caudate and putamen areas. The events in cell differentiation are being studied in cultured substantia nigra neurons and glial cells for insights into why cells die in Parkinson's patients. The effects of growth factors are being examined to see if they can be used to increase survival of dopamine cells in culture.

Tests have been set up to look for dopaminergic toxins or other possible toxic factors in patients' caudate tissue.

A major problem for research and treatment is the difficulty of obtaining healthy fetal tissue. Treating a few patients per year will not make a significant dent in the large population of Parkinson's sufferers. One possible solution is to create an immortalized dopaminergic cell line. Because this may involve viral vectors or oncogenes, methods for preventing the cells from turning cancerous must be ascertained. The cells must also be able to release dopamine in a regulated manner, because too much dopamine is as bad as too little.

Despite its present limitations, fetal tissue transplantation has been shown to restore neurologic function in patients with severe parkinsonism. Research to verify the clinical improvements and to define the factors that are directly responsible for the improvements must proceed. The lifting of the ban on fetal tissue research will hopefully enable research on this disease to go forward more quickly.

Copyright 1994 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK232006

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