12 November 2001. A bold, but also much-criticized, experimental therapy for
Parkinson's disease involves injecting dopaminergic, human embryonic neurons
into a dopamine-depleted brain area of patients in the hopes that the
grafted cells will replenish the missing neurotransmitter. Today at the
Neuroscience meeting, Curt Freed of the University of Colorado, Denver, and
David Eidelberg of North Shore-Long Island Jewish Research Institute told
reporters about the long-term follow up of 40 patients.
First off, it is important to note that this treatment cannot become widely
available unless the scientists find another source of transplant material.
They are now using neurons from only two embryos as opposed to the four
fetuses per patient that were needed when this therapy began but,
ultimately, a continuous supply of neurons or stem cells from a cell line
would be needed. At the same time, however, the procedure is perhaps the
most advanced of many experimental cell therapy approaches currently
underway and as such offers insight into the prospects of this field. Some
patients have been observed for up to seven years.
In a widely noted paper in the New England Journal of Medicine published
last March, Freed and his colleagues reported an interim analysis of 40
patients (Freed et al. 2001). They were enrolled in 1994; since then 22 more
have had the operation, all without immunosuppression. While the transplants
did reverse symptoms in some patients, five had severe, persistent
involuntary movements called dyskinesia that arose years after cell
implantation. Eidelberg used PET imaging to compare dopamine activity in
these five patients to that in patients who did not have dyskinesia.
Eisenberg reports here that his group detected excessive dopamine activity
in the dyskinesia patients. The implanted cells effectively overdosed them.
Eisenberg et al. also found that these patients had a much greater loss of
dopamine transmission (75 percent) in the dorsal, or upper, part of the putamen
(the olive-shaped part of the striatum that received the transplant) than in
the ventral part (30 percent.) That, Eisenberg said, explained the dyskinesia as
the initial 40 patients had received injections into both parts of the
putamen. Future transplant patients will receive smaller numbers of cells
and only into the dorsal part of the putamen.
How bothersome is this side effect? Do patients regret having had the
procedure? Eisenberg said that of the five patients he studied, three
considered it acceptable since they had had such movements prior to surgery.
For two patients, however, who have severe involuntary movements of the
mouth and head, the side effects appear to overshadow the benefits of the
This raises the question whether this expensive treatment offers any
improvement over drug therapy if it generates the same side effects, as does
L-dopa. Moreover, L-dopa, which is known to generate schizophrenic side
effects when given in excess, can easily be adjusted. How about the
transplants? They keep growing and changing over time. Can they be
Freed noted that the patients in this first controlled trial of CNS
transplantation no longer responded well to L-dopa treatment prior to
transplantation. After transplantation, they gradually were weaned off
L-dopa, and they improved. Those whose transplant released too much dopamine
even after they were off L-dopa were successfully treated with a second drug
that interferes with dopamine, he said. Those who needed still further
reduction of dopamine activity in the putamen (two of the five) were treated
with deep brain stimulation, a dopamine-lowering surgery that activates a
separate, dopamine-inhibiting brain area. This means that the transplants'
effects followed a dose-response curve and can therefore be modulated by
more targeted transplantation and subsequent pharmacological management,
In Parkinson's, dopaminergic neurons in the substantia nigra that project to
the striatum gradually die. In fact, about 80 percent are lost by the time
most patients get diagnosed. This creates a dopamine deficit in the putamen
and caudate subareas of the striatum. Some dopamine, however, is also made
in the frontal cortex and, indeed, Parkinson's frequently progresses from
being primarily a movement disorder to becoming a dementing disease (see
story below). Freed noted that a paper under submission will report that
transplantation had no effect on cognition in his patients.-Gabrielle Strobel.
Reference:Ma Y et al. Dyskinesias following dopamine cell implantation for
Parkinson's disease are related to increases in putamen FDOPA uptake. Soc Neuroscience 2001.
Freed CR et al. In double-blind trial, L-dopa responsiveness and not age
predicts outcome of human embryonic dopamine cell transplants for