Re: Parkinson's - Failure of Fetal Cell Implants

From: Jim Fehlinger (fehlinger@home.com)
Date: Thu Mar 08 2001 - 18:12:54 MST


Damien Broderick wrote:
>
> http://www.nytimes.com/2001/03/08/health/08PARK.html?pagewanted=print

Very disappointing. Not too surprising for a first crack at
this sort of thing, I guess (though tragic for some of the
patients -- a sobering lesson for the folks on this list).

The above link will go stale in no time, so I will risk infringement
by including the full text (it deserves to stick around in these
precincts):

March 8, 2001

Parkinson's Research Is Set Back by Failure of Fetal Cell
Implants

By GINA KOLATA

    A carefully controlled study that tried to treat Parkinson's
     disease by implanting cells from aborted fetuses into
     patients' brains not only failed to show an overall benefit
     but also revealed a disastrous side effect, scientists
     report.

In about 15 percent of patients, the cells apparently grew too
well, churning out so much of a chemical that controls movement
that the patients writhed and jerked uncontrollably.

The researchers say that while some patients have similar effects
from taking too high a dose of their Parkinson's drug, in this
case the drugs did not cause the symptoms and there is no way to
remove or deactivate the transplanted cells.

On the researchers' advice, six patients who enrolled in the
study but who had not yet had the implantation operation have
decided to forgo it.

The results, reported today in The New England Journal of
Medicine, are a severe blow to what has been considered a highly
promising avenue of research for treating Parkinson's disease,
Alzheimer's disease and other neurological ailments. The study
indicates that the simple solution of injecting fetal cells into
a patient's brain may not be enough to treat complex diseases
involving nerve cells and connections that are poorly
understood. Some say it is time to go back to the laboratory and
to animals before doing any more operations on humans.

The findings may also fuel the debate over whether it is
appropriate to use tissue from aborted fetuses to treat
diseases. Despite their disappointment, some researchers said
they hoped that the results would not bring fetal cell research
to an abrupt halt. The research has been controversial because
the fetal cells were obtained from abortion clinics.

"This is still our one great hope for a cure," said
Dr. J. William Langston, who is scientific director and chief
executive officer at The Parkinson's Institute in Sunnyvale,
Calif.

Parkinson's disease occurs when cells of the substantia nigra
region in the base of the brain die, for unknown reasons. The
hope was that fetal substantia nigra cells might take over for
them. But, the study showed, in older patients the operation had
no benefit and in some younger patients, the transplants brought
on nightmarish side effects.

Although the paper depicts the patients with the side effects in
impassive clinical terms, doctors who have seen them paint a very
different picture.

Dr. Paul E. Greene, a neurologist at the Columbia University
College of Physicians and Surgeons and a researcher in the study,
said the uncontrollable movements some patients suffered were
"absolutely devastating."

"They chew constantly, their fingers go up and down, their wrists
flex and distend," Dr. Greene said. And the patients writhe and
twist, jerk their heads, fling their arms about.

"It was tragic, catastrophic," he said. "It's a real
nightmare. And we can't selectively turn it off."

One man was so badly affected that he could no longer eat and had
to use a feeding tube, Dr. Greene said. In another, the condition
came and went unpredictably throughout the day, and when it
occurred, the man's speech was unintelligible.

For now, Dr. Greene said, his position is clear: `No more fetal
transplants. We are absolutely and adamantly convinced that this
should be considered for research only. And whether it should be
research in people is an open question."

Dr. Gerald D. Fischbach, who was director of the National
Institute of Neurological Disorders and Stroke, which sponsored
the study, said that while the operation had been promoted by
some neurosurgeons as miraculous, this was the first time it was
rigorously evaluated. It used sham surgery as a comparison, a
controversial and rarely used strategy but one that researchers
felt was necessary to understand the true effects of the
operation.

Dr. Fischbach, who is now dean of the faculty of medicine at the
Columbia University College of Physicians and Surgeons, was the
director of the institute only at the end of the study.

"Ad hoc reports of spectacular results can always occur,"
Dr. Fischbach said. "But if you do these studies systematically,
this is the result you get."

The surgery, he added, "is not the final solution that people
would have hoped going into it."

In the study, researchers, led by Dr. Curt R. Freed of the
University of Colorado Health Sciences Center in Denver and
Dr. Stanley Fahn of the Columbia University College of Physicians
and Surgeons, recruited 40 patients, ages 34 to 75, who had had
Parkinson's disease for an average of 14 years. The patients were
randomly assigned to have substantia nigra cells from four
fetuses implanted in their brains or to have sham surgery, for
comparison.

The surgery took place in Colorado and the patients were
evaluated in New York. The fetal cell surgery involved drilling
four small holes in the patient's forehead and then inserting
long needles through the holes into the brain and injecting fetal
cells. The sham surgery involved drilling the holes but not
injecting needles into the brain. After a year, the patients were
told whether they had the fetal cell surgery and, if not, they
were offered it if they wanted it.

The study's primary measure of success was whether the patients
themselves noticed that they were better, as determined by a
survey that they mailed in a year later but before they knew
whether they had had fetal cell implants or a sham operation. The
study found no difference between the two groups neither
those who had had the fetal cell operation nor those who had had
the sham surgery noticed an improvement in their symptoms.

Other tests, like neurologists' assessments of the patients while
they were taking their medication and the patients' assessments
of their condition in diaries they kept also showed no effect of
the surgery. And there was no difference between the two groups
in the doses of drugs needed to control the disease.

The one glimmer of hope came from assessments by neurologists
before the patients had had their first dose of medication in the
morning. By that measure, the 10 patients under age 60 who had
had the fetal cell implants seemed better than those who had had
sham surgery, with less rigidity, although their tremor was just
as bad.

Dr. Freed hailed that result, saying, "It was a clear-cut
improvement."

And, he added, the fetal cells survived in most patients' brains.

"I would be disappointed if people used a strict clinical trial
approach," Dr. Freed said. "This study is about multiple
phenomena."

Others were less enthusiastic, pointing out that finding
subgroups after the fact who may have benefited suggests a
hypothesis for future studies, not evidence of an effect.

"We try to teach everybody that you have to identify beforehand
what's the primary outcome," said Dr. William Weiner, the
director of the Maryland Parkinson's Disease and Movement
Disorder Center and a professor of neurology at the University of
Maryland School of Medicine in Baltimore, referring to the
measure of success determined before the study began. "In this
case, they picked a subjective assessment by the patients
themselves, which I think is a very good one."

And so, Dr. Weiner said, when the patients noticed no
improvement, "the study was negative."

In addition, Dr. Langston said, even if a subsequent study
confirmed that the surgery had an effect on the condition in
younger patients before they took their medicine in the morning,
and even if there was a way of preventing the terrible side
effect, the operation would still hardly be a
breakthrough. Parkinson's disease is almost always a disease of
the elderly, he noted, adding that well under 10 percent of
patients who would be candidates for the surgery are younger than
60.

The wiggling and writhing movements first emerged a year after
the operation, showing up in five of the younger patients who had
at first appeared to benefit from fetal cell surgery three
who had the operation in the initial phase of the study and two
who had it a year later, when they learned that they had
originally had a sham surgery. While doctors sometimes see such
effects in Parkinson's patients, it is caused by giving too much
of drugs that act like dopamine in the brain. And it can be
controlled by reducing the drugs.

In this case, however, drugs were not the culprit. Even when
doctors took away the drugs, the symptoms persisted.

The fetal implant study had been controversial from the start,
both because it included sham surgery and because it used fetal
tissue from abortions. But many Parkinson's disease experts said
it had to be done because doctors were already offering the
surgery to patients, and charging them for it, at costs of
$40,000 or more, with no evidence that they were helping
them. Yet patients, facing a disease in which brain cells slowly
and inexorably die and in which even the drugs that once
controlled their symptoms of tremor and rigidity would inevitably
fail, took their chances with the operation, thinking they had
little to lose.

Dr. Freed said he was the first in the United States to offer the
treatment, starting in 1988 with a 52-year- old man, who is still
alive although, of course, he also still has Parkinson's disease.

Dr. Freed continued to offer it to paying patients while he was
treating those who were part of the federal study and whose
procedures were paid for by the study. He said he considered
these other operations research because he experimented with
different amounts and placements of fetal cells. He has given
fetal cell implants to 27 patients, he said, with the most recent
operation last October.

Dr. Freed said his group was now implanting less fetal tissue and
putting the tissue in a different area of the brain, hoping to
avoid the devastating side effects. But, he said it would be a
mistake to stop doing the surgery altogether.

"To say that you can't do or shouldn't do human research because
the research has uncertain outcome, I think would be a bad
decision," Dr. Freed said.

Meanwhile, a second federally financed study of the operation is
winding to a close, and some researchers say it is time to go
back to animal studies and learn more about the complex roles of
the brain cells involved in Parkinson's disease.

Dr. Weiner said that if a patient came to him today seeking
advice, he would say: "The bottom line for patients is that human
fetal cell transplants are not currently the best way to go. If
you are willing to pay for them, you can still have them
done. But my advice is you ought not to do this."

                                                 Copyright 2001
                                                 The New York
                                                 Times Company



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