Fetal Cell Grafts for Parkinson’s Win Converts

Terrie Wenc jogs five miles every day--not unusual for a 47-year-old woman in trim condition. But Wenc is not your average jogger.

Less than a year ago, she could not even drive, much less jog. Parkinson’s disease had frozen her into immobility for several hours every day. She had to give up the beauty salon she owned, forfeited two houses and a car because of her medical expenses, and faced a future of despair.

Then in May, she received a fetal cell graft at Los Angeles’ Hospital of the Good Samaritan, one of only four medical centers in the United States that perform the controversial procedure.

Today, she is not only jogging and playing racquetball, but she is also studying for a real estate license and planning to write a book about her experiences.

Her recovery from Parkinson’s, doctors say, is a sign of an approaching new era in the treatment of the incapacitating disease. Furthermore, it typifies the growing success of fetal transplants as doctors refine their techniques and learn who are the best transplant candidates.

Encouraged by early results, surgeons worldwide are gearing up to use the technique on more patients. In addition, researchers have begun studies to explore the use of genetically engineered cells to replace the fetal cells, which are controversial and in short supply. Others are laying plans to use fetal grafts to treat other disorders, including Huntington’s disease and Alzheimer’s disease.

Dr. Deane (Skip) Jacques and his colleagues at Good Samaritan have done fetal grafts on 15 patients, and only two have not shown improvement--results typical of those being seen at other centers. Jacques and his colleagues have been close-mouthed about their research in the past because of the controversy about the use of fetal tissues from abortions.

But their encouraging results, combined with the lifting last year of the federal moratorium on fetal cell research, mean “we don’t have to hide anymore,” Jacques said.

Because of the successes by Jacques and others, several more U.S. groups are gearing up to conduct the grafts. “We’re going to see more and more of this because it is so effective,” Jacques said.

“Fetal tissue grafting will become the major area of development in neurosurgery,” said Dr. Edward Hitchcock of the University of Birmingham in England, who has operated on 48 patients.

Ironically, the government’s lifting of a ban on federal funding for fetal tissue research has created a new problem for researchers--a shortage of funding for the costly procedure.

“When President Clinton lifted the ban last January, many of our funding sources dried up because they thought the federal government would take over funding,” said Dr. D. Eugene Redmond of Yale University.

But the government agency that funds most medical research--the National Institutes of Health--has funded only one program, at the University of Colorado. Programs such as Redmond’s and Jacques’ at Good Samaritan were left little money to pay for the experimental surgery. “That’s created intense competition for money,” Redmond said.

Impatient with funding delays, some patients who would ordinarily have received the experimental surgery at no cost have paid for the $40,000 procedure themselves. Wenc’s friends and former customers raised the money for her surgery in three months.

The patients are highly motivated to seek the surgery because of the severe disabling effects of Parkinson’s disease, which affects between 500,000 and 1 million Americans, most of them over age 55. The disorder, whose cause is unknown, is characterized by tremors and rigidity in the limbs and loss of muscle control. As many as a third of Parkinson’s patients also develop dementia, an impairment of thought processes.

Parkinson’s results from the death of brain cells that produce a neurotransmitter called dopamine, which plays a key role in transmitting commands from the muscle control centers. The disorder is treated with a drug called L-dopa, which alleviates symptoms by producing dopamine in the brain. But many patients do not respond to L-dopa and most eventually become resistant to its effects.

Dale Bahn, a high school mathematics teacher in the Minneapolis suburb of Anoka, who began developing Parkinson’s symptoms at age 34, showed a typical disease course. L-dopa helped for a while, but by the time he was 48, he had to quit his job. “The tremors were the worst part, but I couldn’t walk right either,” he said. “I would freeze in doorways and hallways. It would be almost total immobility.”

Bahn heard about the Good Samaritan program through a computer bulletin board operated by a Parkinson’s support group. After visiting Good Samaritan, he was accepted into the program.

His surgery was performed Sept. 3, 1992. “At first, I was in a terrible state,” he said. “I couldn’t walk or do anything else.” It took nearly eight weeks before he was back to the condition he had been in at the time of the surgery. “Then I slowly started noticing things improving. It was two steps forward for every step back.” Today, he drives his car, works around the house and leads what he considers a “largely normal” life.

Although researchers have known for nearly two decades that grafting dopamine-producing cells into the brain can relieve Parkinson-like symptoms in animals, it was not until 1986 that Dr. Ignacio Navarro Madrazo, now at the Instituto Mexicano del Seguro Social in Mexico City, first performed the procedure in humans. Madrazo grafted dopamine-producing cells from the Parkinson patients’ adrenal gland, a walnut-sized organ above the kidney, into the brains of the patients and observed a distinct improvement in symptoms.

Madrazo’s first patient was Joseluis Meza, then a 33-year-old Mexico City resident who could not speak clearly, walk, dress, bathe or feed himself without help. After the surgery, Meza recovered all those abilities--to the point where he could begin working again and play soccer with his 5-year-old son, Mario.

Seven years later, Madrazo said, Meza has deteriorated somewhat, but he is still able to take care of himself and “he is still much better than he was before the surgery.”

Madrazo has performed 90 adrenal transplants, and American researchers have performed at least another 120, according to Dr. Roy A. E. Bakay of Emory University, who maintains a registry of brain grafts.

Madrazo’s results with adrenal grafts are probably typical of the several hundred performed throughout the rest of the world, experts agree. Overall, “two-thirds of the patients had beneficial effects” from the surgery, Madrazo said at a recent symposium sponsored by Good Samaritan. But the procedure has now largely been rendered obsolete by fetal transplants, and results of his limited studies with fetal tissues have been even better, Madrazo said.

“Fetal tissue has a very, very clear beneficial effect,” he said. Because abortion is illegal in Mexico, Madrazo can treat Parkinson’s patients only with fetal tissue obtained in spontaneous abortions. He has thus treated only four patients with fetal tissue.

Worldwide data on fetal tissue grafts is sparse because many researchers are slow in reporting their data to the registry, Bakay said. But the statistics are more readily available in the United States. In addition to Good Samaritan’s 15 patients, Yale’s Redmond has done 15, Dr. Curt Freed of the University of Colorado Medical Center in Denver has done 16 and Dr. Warren Olanow of the University of South Florida has performed four. Dr. Robert Iacono of the Loma Linda Medical Center has also performed fetal tissue grafts on 14 patients, though the surgeries were conducted in Hong Kong and China.

So far, the results have been dramatic, according to the surgeons. “These patients were severe before we started on them,” Jacques said. “They were very sick, most of them were wheelchair-bound. Now most are quite a bit better.”

In the absence of effective new drugs or other treatments, Freed said, “only transplants are likely to cure Parkinson’s disease . . . or make a difference” in the patients’ lives. With the transplants, said Dr. John R. Sladek Jr. of the University of Chicago Medical School, “We have the opportunity to help truly sick people.”

Despite successes with the surgery, many questions remain. Surgeons are not in agreement on the best sites to implant the fetal cells within the brain or on how much tissue to use for optimum results. Some researchers question whether the fetal cells provide any benefit at all, arguing that the operation itself may stimulate the regeneration of dying cells, whether fetal tissues are implanted or not.

To address these questions, NIH earlier this month awarded a $4.5-million grant to Freed and his Colorado colleagues to conduct a controlled clinical trial of fetal tissue transplants. For the first time, some patients will receive sham operations--identical to the fetal tissue implant, but with saline solution injected rather than fetal cells--so that researchers can determine the effects of the surgery itself.

The team will also graft fetal tissue at different sites in the brain to learn which location works best. Freed believes that the study will provide a blueprint for a uniform, effective way to conduct the surgery.

But NIH is unlikely to award any other grants in the near future, researchers say--a situation that is slowing the use of the procedure. To get around the money shortfall, some researchers, such as the Good Samaritan team, are having patients pay for the surgery themselves, a process that many physicians consider dubious and some consider unethical.

Patients are not normally charged for experimental procedures or drugs; the costs are borne by the government or the company that developed the drug or treatment. Ethicists fear that charging patients biases the results of such trials because subjects are selected based on their ability to pay rather than on the appropriateness of the procedure or the likelihood that they will benefit from it. “There are major methodological questions that can only be worked out in a research context (like Freed’s new study),” Redmond said.

Despite the promise of fetal tissue grafts, some researchers, such as Dr. Charles Markham of UCLA, see it “more as a pointer to even better techniques in the future.” Ultimately, they envision the development of genetically engineered cells that can be grown in large quantities in the laboratory and programmed to produce not only larger quantities of dopamine, but also growth factors that might stimulate the repair of damaged brain cells.

Several research teams are developing such cells, but their first use in humans is probably at least two years off.

Researchers are setting their sights on other diseases as well. Madrazo has performed fetal tissue implants on two Huntington’s patients. The surgery has not reversed the disease’s symptoms, he said, but it has significantly slowed the progression of the disorder in both cases.

European researchers are also very close to using fetal tissue grafts to treat Alzheimer’s disease, possibly within the next couple of months. The widespread adoption of fetal tissue transplants for other diseases could change the face of neurosurgery, experts agree.

But for patients such as Wenc, the future has arrived. “I have a new lease on life,” she said. “It’s like being reborn.”

Treating Parknison’s

Fetal tissue transplants have reversed the most serious symptoms of Parkinson’s disease, allowing people who were wheelchair-bound and unable to take care of themselves to live more normal lives. The controversial operation has been performed on about 200 patients, including 50 in the United States.

Surgery: Parkinson’s results from the death of brain cells that secrete dopamine, a messenger that is important in controlling movements. In the surgery, dopamine-secreting cells from fetuses are inserted into the brain where cells have died. The surgery must be done very precisely, to ensure that the cells reach the proper location and to minimize damage to other brain cells.

Recovery: If the cells are injected into multiple sites, recovery can take as long as two months. Beneficial effects from surgery generally begin to appear after about three months.

Availability: The surgery is performed at only four U.S. institutions: Hospital of the Good Samaritan in Los Angeles, the University of Colorado School of Medicine, Yale University School of Medicine and the University of South Florida.

Cost: Typically, $40,000 to $50,000. It is not generally covered by insurance.