Fetal Brain Cell Transplants Benefit Some Patients with Parkinson's
Placebo-controlled Surgery Trials
In the first double-blind, placebo-controlled surgical trial testing the
safety and effectiveness of fetal dopamine cell implantation for the
treatment of Parkinson's disease, most patients who received the
implants showed growth of the new brain cells, and many had
improvement in their symptoms, though some had long-term
complications.
Pope John Paul II is suffering from
Parkinson's disease.
The study, which is being
published tomorrow in the New
England Journal of Medicine, shows
that transplanted patients were
better able to move and perform
other activities before taking their
daily medications, compared to patients who received the placebo
operation. Among the 40 patients who participated in the trial, 20
received the transplanted fetal cells, and 20 experienced a placebo
surgery, in which there was no actual needle penetration of the
brain.
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Results of the study showed that the transplants grew in 85 percent
of patients regardless of age. Standardized tests of Parkinson's
disease performed one year after surgery revealed improvements in
transplant patients age 60 or younger, but not in older patients.
After three years, improvement in the younger patients was greater
than after one year. About 15 percent of patients who had initially
improved later experienced a recurrence of excess, abnormal
movements even after reduction or elimination of levodopa
treatment, suggesting that the transplants produced more dopamine
than optimal for those patients.
"The results of our study show that fetal dopamine cells have
potential value for treating patients with Parkinson's disease," said
Curt Freed, MD, professor and head of the Division of Clinical
Pharmacology and Toxicology, and director of the Neuroscience
Program at the University of Colorado Health Sciences Center. "This
research is an important milepost for the ongoing development of
cell transplantation as a treatment for Parkinson's. We are now
testing ways to produce a better and more uniform response in
individual patients and to understand why older patients are more
resistant to the effects of the transplant."
In an accompanying editorial in the NEJM, Gerald Fischbach, MD,
former director of the National Institute of Neurological Disorders
and Stroke (NINDS), and Guy M. McKhann, MD, NINDS associate
director for clinical research, recommend caution in interpreting the
results of the study, writing: "Disabling dyskinesias appeared in 15
percent of the patients who receive implants, but only in the second
year after surgery. These severe side effects appeared in the same
patients who had improved during the first year after surgery, and
they persisted despite the lowering of the dose of levodopa." The
commentators go on to point to the value of the study as an
important step in research toward effective therapy for Parkinson's
patients.
The study was conducted jointly by researchers at the CU-Health
Sciences Center, Denver; Columbia Presbyterian Center of New York
Presbyterian Hospital, New York; Columbia University College of
Physicians & Surgeons, New York, and North Shore University
Hospital, Manhasset, New York.
Dr. Freed and his neurosurgical colleague, Robert Breeze, MD,
professor of neurosurgery at the CU-Health Sciences Center, have
been researching fetal cell transplantation for more than a decade.
In 1988, they performed the first fetal cell implant for Parkinson's
disease in the United States.
The unique double-blind surgical experiment was designed in
collaboration with Stanley Fahn, MD, director of the Center for
Parkinson's Disease and Other Movement Disorders at New York
Presbyterian Hospital, and H. Houston Merritt Professor at the
Columbia University College of Physicians & Surgeons; Paul Greene,
MD, assistant professor of neurology at the Columbia University
College of Physicians & Surgeons and assistant attending neurologist
at New York Presbyterian Hospital; and David Eidelberg, MD, director
of the Functional Brain Imaging Laboratory, director of the
Movement Disorder Center at North Shore University Hospital and
director of the Movement Disorders Program at the New York Weill
Cornell Center of New York Presbyterian Hospital.
"While placebo-controlled drug trials have long been the gold
standard to test the value of a new drug, only a few placebocontrolled surgery trials have been conducted," Dr. Fahn said. "In
Parkinson's disease, about 30 percent of patients feel better after
getting a placebo drug. We found that some patients who had
placebo surgery did feel their Parkinson's disease had improved."
Dr. Eidelberg said: "This is a landmark study in the field of
Parkinson's research. Using new brain imaging techniques, we are
able to understand how clinical improvement is influenced by fetal
cell implantation in individual patients."
Forty patients were enrolled in this study, which began in 1995 and
was funded by $9 million in National Institutes of Health (NIH)
grants. Nineteen women and 21 men were enrolled in the trial. Half
of the patients were age 60 or under, and the average duration of
disease was 13.8 years. The patients were randomized into two
groups. Half of the patients had fetal dopamine cells implanted in
four locations in their brains through a surgical procedure performed
under local anesthesia. Patients in the other group had a placebosurgery procedure, in which Dr. Breeze drilled holes in their skulls
without penetrating the brain, and no fetal cells were implanted.
Drs. Fahn and Greene enrolled the patients and conducted
evaluations without knowing which operation the patients received.
They examined patients both on and off their standard medications.
They found that the younger group of transplant patients had
significant improvement in standardized tests known as the Unified
Parkinson's Disease Rating Scale and the Schwab and England
activities for daily living scale. Improvement was seen in tests done
in the morning before patients had their first dose of levodopa,
indicating that the transplants could provide the dopamine needed
for movement.
Dr. Eidelberg and his team at North Shore evaluated the patients
using a brain imaging technique called Positron Emission
Tomography (PET) to study the growth of the transplants. PET scans
were conducted prior to surgery and at 12 months after the
procedure.
Without knowing which patients received the placebo operation and
which received the transplants, Dr. Eidelberg detected growth of the
implanted cells in 85 percent of the transplant patients. Only one of
the 20 placebo-surgery patients was wrongly thought to have had
transplant growth by PET scan.
Autopsies of two patients who died of causes unrelated to the
transplant operation showed significant growth of the implanted
tissue.
After one year of evaluation and data collection, individual patients
and their doctors were then told which procedure they had received.
Those who had the placebo operation were given the choice of
receiving the fetal implants. Most of the placebo-surgery patients
decided to have the transplants (14 out of 20), but as the follow-up
and data collection showed the results to be variable, the six
remaining patients were advised against transplantation until further
research has been completed.
Parkinson's disease is a chronic neurological disease that impairs
mobility. The disease results from the progressive loss of a small
number of nerve cells that produce dopamine, a chemical
neurotransmitter in the brain that is required for normal movement.
While treatment with drugs such as levodopa has provided
substantial relief for most patients with the disease, the drugs tend
to lose their effectiveness after five-to-10 years of use. The goal of
the fetal tissue implants is to replace the lost dopamine-producing
cells and restore more normal movement to the patients.
Early transplant studies showed promising results in some patients
with advanced Parkinson's disease, leading to the collaborative fetal
neural transplant program. Future progress in cell transplantation for
Parkinson's disease will come from improving survival and growth of
dopamine neurons. Equally important is understanding which patients
are most likely to respond to transplant. Laboratory production of
dopamine cells may prove possible. Such a development could make
neurotransplantation available for all patients who could benefit from
the procedure. http://hdlighthouse.org/see/xplant/pd.htm
FETAL BRAIN CELL TRANSPLANTS
BENEFIT SOME PATIENTS WITH PARKINSON'S
New York, NY, April 21, 1999 - Fetal cell implants help some patients with Parkinson's
disease, especially those over 60. In the first double-blind, placebo-controlled surgical
trial testing the safety and effectiveness of fetal dopamine cell implants for the treatment
of Parkinson's disease, many patients who received the implants showed growth of the
new brain cells and improvement in their symptoms. Compared to patients who received
the placebo operation, transplanted patients were better able to move and perform other
activities before taking their medications. The study also showed that there was a great
deal of variability in the transplant outcome, so that the benefit for any individual patient
was unpredictable. When patients were grouped by age, those under age 60 benefited,
while those over age 60 did not.
Results of the study were presented April 21, 1999, at the American Academy of
Neurology meeting in Toronto. The study was conducted jointly by researchers at the
University of Colorado Health Sciences Center, Denver; Columbia Presbyterian Center
of New York Presbyterian Hospital, New York; Columbia University College of
Physicians & Surgeons, New York, and North Shore University Hospital, Manhasset,
New York.
"The results of the placebo-controlled study are critical for guiding our research on
improving cell transplantation as a treatment for Parkinson's disease," said Curt Freed,
M.D., professor and director of the Division of Clinical Pharmacology and Toxicology,
and director of the Neuroscience Program at the CU-Health Sciences Center. "We are
now testing ways to produce a more uniform response and to understand why older
patients are more resistant to the effects of the transplant."
Dr. Freed and his neurosurgical colleague, Robert Breeze, M.D., associate professor of
neurosurgery at the CU-Health Science Center, have been researching fetal cell
transplantation in the treatment of Parkinson's disease for more than a decade. In 1988,
they performed the first fetal cell implant in the United States.
The unique double-blind surgical experiment was designed in collaboration with Stanley
Fahn, M.D., director of the Center for Parkinson's Disease and Other Movement
Disorders at New York Presbyterian Hospital, and H. Houston Merritt Professor at the
Columbia University College of Physicians & Surgeons; Paul Greene, M.D., assistant
professor of neurology at the Columbia University College of Physicians & Surgeons and
assistant attending neurologist at New York Presbyterian Hospital; and David Eidelberg,
M.D., director of the Functional Brain Imaging Laboratory, director of the Movement
Disorder Center at North Shore University Hospital and director of the Movement
Disorders Program at the New York Weill Cornell Center of New York Presbyterian
Hospital.
"While placebo-controlled drug trials have long been the gold standard to test the value
of a new drug, only a few placebo-controlled surgical trials have been conducted," Dr.
Fahn said. "In Parkinson's disease, about 30 percent of patients feel better after getting a
placebo drug. We found that some patients who had placebo surgery did feel their
Parkinson's disease had improved."
Dr. Eidelberg said: "This is a landmark study in the field of Parkinson's research. Using
new brain imaging techniques, we are able to understand how clinical improvement is
influenced by fetal cell implantation in individual patients."
Forty patients were enrolled in this study, which began in 1995 and was funded by a $4.8
million National Institutes of Health (NIH) grant. The patients were randomized into two
groups. Half of the patients had fetal cells implanted in four locations in their brains
through a surgical procedure performed under local anesthesia. Patients in the other
group had a similar procedure, in which Dr. Breeze drilled holes in their skulls without
penetrating the brain, and no fetal cells were implanted.
Drs. Fahn and Greene enrolled the patients and conducted evaluations without knowing
which operation the patients received. They examined patients both on and off their
standard medications. Dr. Eidelberg and his team at North Shore, none of whom knew
which patients had received the transplant, then evaluated the patients using a brain
imaging technique called Positron Emission Tomography (PET) to study the growth of
transplants. Dr. Eidelberg also is director of the PET Imaging Center at North Shore.
Nineteen women and 21 men were enrolled in the trial. Half of the patients were over age
60; the average duration of disease was 13.8 years. PET scans were conducted prior to
surgery and at 12 months after the procedure. Without knowing which patients received
the placebo operation and which received the transplants, Dr. Eidelberg detected
significant growth of the implanted cells in about two-thirds of the transplant patients and
detected some growth in 17 of the 20 transplant patients. Only one of the 20 placebo
patients was wrongly thought to have had transplant growth by PET scan.
Autopsies of two patients who died of causes unrelated to the transplant operation
showed significant growth of the implanted tissue.
After one year of evaluation and data collection, individual patients and their doctors
were then told which procedure they had received. Those who had the placebo operation
were given the choice of receiving the fetal implants. Nearly all placebo patients have
decided to have the tissue implant.
Parkinson"s disease is a chronic, neurologic disease that impairs mobility. The disease
results from the progressive loss of a small number of nerve cells that produce dopamine.
While treatment with drugs such as L-dopa has provided substantial relief for most
patients with Parkinson"s disease, the drugs tend to lose their effectiveness after five
years of use. The goal of the fetal tissue implants is to replace the lost dopamineproducing cells and restore more normal movement to the patients.
Early studies showed promising results in some patients with advanced Parkinson"s
disease, leading to the collaborative fetal neural transplant program. The program was the
first to receive an NIH grant to study fetal tissue implants after a federal ban on funding
fetal tissue research was lifted in January 1993.
College of Physicians and Surgeons at Columbia-Presbyterian Medical Center
Office of Public Relations
630 West 168th Street
P&S Box #37
New York, NY 10032
http://www.cumc.columbia.edu/news/press_releases/04211999FETALBRA.html
Think again:
Transplanting fetal brain cells to treat Parkinson's disease "disastrous"
New Scientists n.76, 17mar01
A US experiment which produced "disastrous" results after fetal cells were transplanted
into the brains of Parkinson's disease sufferers has been severely criticised by
international experts.
Five of 20 patients were left with uncontrollable and untreatable jerky movements, which
the US team says are caused by the new dopamine-producing cells going into overdrive.
Previous trials of fetal cell transplants in Parkinson's sufferers in Europe have relieved
symptoms in many patients without producing severe side effects. These new "absolutely
devastating" results mean fetal transplant experiments have to go right back to the
drawing board, said Paul Greene, a neurologist at Columbia University in New York, and
one of the researchers.
But leading European Parkinson's experts say the US experiment was seriously flawed.
"This study unfortunately used a technique different to those used in previous primate
and human studies," says Lucy Annett of Cambridge University, who has performed
transplants in primates. "It had not been properly validated by animal studies."
Anders Björklund, a world leader in human fetal cell transplants at Lund University in
Sweden, told New Scientist: "We are convinced this study has no implications for
ongoing fetal transplant Parkinson's programmes."
Sham surgery
Over 20 European scientists wrote to the journal Science seven years ago expressing their
concern that the funding of a large trial for this technique ignored other, perhaps more
promising, approaches.
The trial, conducted by a team from Columbia University, involved transplanting fetal
brain tissue into the brains of 20 long term Parkinson's sufferers. Controversially, 20
other patients received sham surgery.
Some of the patients showed no improvement in symptoms. For others, the improvements
were slight. But after one year, the patients that had showed the most improvement began
to develop severe dyskenesia - uncontrollable jerky movements. These were more intense
than their original symptoms.
The Columbia team say the embryonic cells had gone into overdrive, and were producing
too much dopamine. There is no way to turn these cells off.
Technical trouble
Björklund says other experiments using much higher volumes of fetal tissue have not
produced these side effects. He says technical problems with the trial make it impossible
to estimate how many of the dopamine-producing cells reached the vital part of the
patients' brains.
The surgical technique itself was unusual, he says. The injections were made through the
frontal cortex, requiring a long needle. "There are concerns that the tissue may have
spilled over into the frontal cortex and have unpredictable results," he says.
Long term storage of the fetal tissue before transplant, and a lack of immuno-suppressive
drugs, could also affect the results, he says.
Björklund says the study does not in any way dim hopes to use stem cells to cure
Parkinson's. Stem cell experiments in mice have already reported good results.
"Using stem cells will make it possible to carefully control the amounts of dopamineproducing tissue being transplanted," he says.
Science (vol 263, p 737)
http://www.mindfully.org/GE/Fetal-Brain-Cells.htm