Cell Therapy for Parkinson's Disease
Parkinson's disease is characterized by the progressive loss of dopamine
neurons in the substantia nigra of the midbrain.
These neurons project widely throughout the cerebral hemispheres, but the
motor symptoms of Parkinson's disease -- bradykinesia, muscle rigidity, and
resting tremor -- are almost certainly due to the loss of dopamine nerve
terminals in the caudate and putamen nuclei (the striatum) of the basal
ganglia and the unbalancing of circuits required for coordinated movement.
One of the therapeutic successes of clinical neurology has been the use of
levodopa, the precursor of dopamine, in patients with Parkinson's disease.
In nearly all patients, the reversal of symptoms is truly remarkable.
However, dopamine replacement does not slow the rate of loss of neurons,
and the beneficial effects wear off with time.
Some patients become less responsive to medication; others become
hypersensitive, and abnormal movements (dyskinesias) develop.
These unsatisfactory outcomes have led to development of dopamine-receptor
agonists and surgical approaches that include pallidotomy and deep-brain
stimulation of the globus pallidus, the thalamus, or the subthalamic
nuclei. (1,2)
There have also been attempts to transplant precursors of dopaminergic
nerve cells directly into the striatum. (3)
The study reported by Freed et al. (4) in this issue of the Journal is the
latest in a series of attempts to treat Parkinson's disease by
transplanting precursors of dopaminergic nerve cells in fragments of
mesencephalon isolated from human fetuses 6 to 10 weeks after conception.
Nearly all previous reports describe moderate improvement in the motor
symptoms in a subgroup of patients.
These results are remarkable, considering the complexity of the circuits in
the striatum and the rest of the basal ganglia and the lack of standards
regarding the amount and handling of tissue to be transplanted, the
placement (caudate nucleus or putamen; unilateral transplantation or
bilateral transplantation), the criteria for the selection of patients, and
the duration of follow-up.
It is encouraging that some of the implanted cells survive and
differentiate, as demonstrated by positron-emission tomography (PET) or by
histologic examination.
The trial conducted by Freed et al. is the first prospective study
comparing a transplantation group with a control group.
In the patients in the control group, burr holes were drilled through the
cranium, but the dura was not penetrated and no cells were implanted.
The surgical team and statisticians were aware of the treatment assignment
of each patient, but the patients and examining physicians were not.
The trial also differed from other studies in important technical details.
The fragments of fetal mesencephalic tissue were dissociated in a cell
suspension, and the cells were maintained in vitro before implantation,
perhaps contributing to their survival in vivo in the absence of
immunosuppressive therapy.
The use of placebo ("sham") surgery has triggered a spirited debate. (5)
Rather than adopt a general policy regarding placebo surgery, one must
weigh for each study the safety of such surgery against the importance of
the results.
The debate should be informed by the realization that the results in the
transplantation group in the trial by Freed et al. could not have been
interpreted fully without analysis of the control group.
After one year, patients younger than 60 years old in the transplantation
group had a small decrease in rigidity and bradykinesia but no change in
tremor or gait.
Improvement was detected only early in the morning after the patients had
been without medication overnight.
No improvement was evident when the patients were at their best, soon after
a dose of medication.
For other outcomes, including the primary one, the score on a global
self-rating scale, no benefit was documented at any time of day in any age
group.
PET studies with 18F-fluorodopa revealed that the transplants contained
competent dopamine nerve terminals.
However, there was no correlation between these findings on imaging studies
and motor improvement.
Disabling dyskinesias appeared in 15 percent of the patients who received
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.
Dyskinesias were noted in earlier open trials, but they usually subsided
when doses of medication were reduced.
One of the most important lessons from this study is that one year of
follow-up is not sufficient for an evaluation of nerve-cell transplantation.
Neural plasticity works at mysteriously different rates, so long-term
outcome must be evaluated.
To reach a consensus about therapies involving the implantation of tissue
or cells, we must learn more about the circuits within the basal ganglia
and their extrinsic connections. (6)
Transplanted dopaminergic neurons are said to "innervate" targets in the
putamen, but this term is used loosely, since precise measures of synaptic
function are not available.
We do not know how dopamine affects the firing of individual neurons or the
function of particular circuits.
It is unlikely, for both practical and biologic reasons, that
transplantation of fragments of embryonic tissue will be the therapy of the
future.
In the present study, tissue from the midbrain of two embryos was injected
on each side of the brain in each patient.
Parkinson's disease is not a rare disorder: estimates of prevalence in the
United States range between 700,000 and 1 million.
The number of fetuses required would be staggering, even if only a small
proportion of the patients were to receive transplants.
Moreover, heterogeneity within tissue fragments is a major barrier to
reproducibility.
The Food and Drug Administration will certainly require standardization of
the preparations of cells.
Immortalized cell lines are our best hope for the development of cells as
realistic and reliable therapeutic agents.
The use of cell lines derived from pluripotent human fetal or embryonic
stem cells poses profound ethical questions, (7,8) but they are currently
the most promising therapeutic possibilities.
Successful transplantation of stem cells has already been achieved in
animal models of Parkinson's disease, motor neuron disease, and spinal cord
injury. Other sources of stem cells, including adult brains and bone
marrow, are under investigation, but their ability to proliferate and the
diversity of their offspring remain unknown.
To consider the use of transplanted cells as a treatment for Parkinson's
disease -- whether they are pluripotent stem cells, more restricted
precursors, or differentiated neurons -- we must know more about their
molecular composition.
In addition to dopamine, such neurons probably manufacture molecules that
influence neuronal proliferation, migration, differentiation, and survival.
All these functions are at risk in Parkinson's disease.
Also, the role of electrical-impulse activity may be important, but we know
little about the functional state of the implanted cells.
As the present study indicates, mere survival is not enough.
The promise of cell therapies has captured the imagination of scientists,
patients, and other members of the public. (9)
Symptomatic treatments are available, but we have not yet reversed the
course of any neurodegenerative disorder.
The brain is a most complex structure, so incremental results on the way to
cures are to be welcomed rather than dismissed as less than perfect.
Gerald D. Fischbach, M.D.
Guy M. McKhann, M.D.
National Institute of Neurological Disorders and Stroke
Bethesda, MD 20892
The New England Journal of Medicine
March 8, 2001
Vol. 344, No. 10
Copyright 2001 by the Massachusetts Medical Society.
All rights reserved.
http://www.nejm.org/content/2001/0344/0010/0763.asp
janet paterson, an akinetic rigid subtype parkie
53 now / 44 dx cd / 43 onset cd / 41 dx pd / 37 onset pd
TEL: 613 256 8340 SMAIL: PO Box 171 Almonte Ontario K0A 1A0 Canada
EMAIL: [log in to unmask] URL: http://www.geocities.com/janet313/
