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Dopaminergic transplantation for parkinson's disease Current status and future prospects.

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POINT OF VIEW
Dopaminergic Transplantation for
Parkinson’s Disease: Current Status and
Future Prospects
C. Warren Olanow, MD, FRCPC,1,2 Jeffrey H. Kordower, PhD,3 Anthony E. Lang, MD,4 and
Jose A. Obeso, MD5
Cell-based therapies that involve transplantation into the striatum of dopaminergic cells have attracted considerable interest as
possible treatments for Parkinson’s disease (PD). However, all double-blind, sham-controlled, studies have failed to meet their
primary endpoints, and transplantation of dopamine cells derived from the fetal mesencephalon is associated with a potentially
disabling form of dyskinesia that persists even after withdrawal of levodopa (off-medication dyskinesia). In addition, disability in
advanced patients primarily results from features such as gait dysfunction, freezing, falling, and dementia, which are likely due
to nondopaminergic pathology. These features are not adequately controlled with dopaminergic therapies and are thus unlikely
to respond to dopaminergic grafts. More recently, implanted dopamine neurons have been found to contain Lewy bodies,
suggesting that they are dysfunctional and may have been affected by the PD pathological process. Collectively, these findings
do not bode well for the short-term future of cell-based dopaminergic therapies in PD.
Ann Neurol 2009;66:591–596
Parkinson’s disease (PD) is characterized by degeneration of dopamine neurons in the substantia nigra pars
compacta (SNc), coupled with the presence of intracellular proteinaceous inclusions known as Lewy bodies.
Current treatment is primarily based on a dopamine
replacement strategy using the dopamine pro-drug,
levodopa.1 While levodopa remains the most effective
therapy for the classic motor features of the illness,
chronic treatment is complicated by wearing off and
dyskinesia. Further, disease progression is associated
with the development of features such as freezing, falling, and dementia that are not satisfactorily controlled
with current medical or surgical therapies. The possibility that transplantation of dopaminergic neurons derived from sources such as the fetal mesencephalon or
stem cells might be a solution to these problems has
attracted considerable interest in both the scientific and
lay communities. However, the failure of double-blind,
sham-controlled trials testing transplantation of fetal
nigral cells,2,3 fetal porcine nigral cells, and retinal pigmented epithelial (RPE) cells (C.W.O., personal obser-
vations), plus reports describing the emergence of a potentially disabling form of dyskinesia in some
transplantation patients,3– 6 has slowed clinical
progress. More recently, we and others have found that
fetal dopamine neurons transplanted 11 to 14 years
earlier had decreased staining for the dopamine transporter (DAT) and contained intracellular inclusions
identical to Lewy bodies (Fig 1), suggesting that they
may have been affected by the PD pathologic process.7–9 These findings warrant a reexamination of the
potential for dopaminergic cell-based therapies to offer
a viable treatment for PD.
From the Departments of 1Neurology and 2Neuroscience, Mount
Sinai School of Medicine, New York, NY; 3Department of Neurological Sciences, Rush Medical Center, Chicago, IL; 4Division of
Neurology, University of Toronto, Toronto, Ontario, Canada; and
5
Department of Neurology, and Neuroscience Division, Clinica
Universitaria and Medical School and CIMA, University of Navarra
and CIBERNED, Pamplona, Spain.
Potential conflicts of interest: Dr C. Warren Olanow, Dr Jeffrey
Kordower, and Dr Anthony Lang have served as consultants to Ceregene, Inc.; Dr Lang has also served as a consultant for BoerhingerIngelheim, Novartis, Solvay, Teva; and Dr Olanow has also served
as a consultant to Novartis/Orion, Teva, Solvay, Merck Serono, and
Boehringer Ingleheim.
Address correspondence to Dr C. Warren Olanow, Department of
Neurology, Mount Sinai School of Medicine, Annenberg 14-94,
One Gustave L. Levy Place, New York, NY 10029. E-mail:
warren.olanow@mssm.edu
Received Mar 24, 2009, and in revised form May 13. Accepted for
publication May 18, 2009. Published online, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21778
Dopamine Cell Transplantation
Transplantation of dopaminergic cells into the striatum
has been investigated as a possible therapy for PD
based on their potential to replace those cells that are
lost as a result of the neurodegenerative process in a
more physiologic manner than can be accomplished
with oral therapies, so as to maximize clinical benefits
while avoiding motor complications. Laboratory stud-
© 2009 American Neurological Association
591
Fig 1. Ubiquitin-stained sections from a PD patient who died 14 years after an intraputamenal fetal nigral transplant.7 (A) Lowpower and (B) high-power photomicrographs of illustrating a Lewy body in a grafted dopamine neuron that is indistinguishable
from (C) low-power and (D) high-power photomicrographs of a Lewy body in a dopamine neuron in the substantia nigra pars
compacta of the same individual. Scale bar shown in (D) represents the following magnifications: (A, C) ⫽ 25␮m; (B, D) ⫽
10␮m. It is noteworthy that inclusions in both graft and host nigra also stained comparably for alpha synuclein and thioflavin-S,
providing further evidence that inclusions in both nigra and implanted neurons are Lewy bodies.
ies have demonstrated that implanted dopaminergic
cells can survive, reinnervate the striatum, and improve
motor function in rodent and primate models of PD.10
Open-label trials have reported clinical benefit with
transplantation of dopaminergic cells derived from fetal
mesencephalon, carotid body, and RPE cells in patients
with advanced PD.11–15 Further evidence of increased
dopaminergic activity following transplantation has
been demonstrated by positron emission tomography16
and postmortem studies showing evidence of robust
graft survival with extensive reinnervation of the striatum.17 However, double-blind, sham-controlled trials
of fetal nigral transplantation,2,3 and double-blind,
sham-controlled trials of fetal porcine nigral transplantation and RPE cells, which have not yet been formally
published (C.W.O., personal observations), each failed
to demonstrate superiority over placebo with respect to
their primary endpoints. Long-term open-label
follow-up studies suggest that individual transplantation patients have done very well and in some instances
can even be maintained with minimal or even no levodopa.18 Further, post hoc analyses performed in the
double-blind fetal nigral trials have reported significant
benefits in subgroups of patients who were less than 60
years of age2 or had milder disease at baseline.3 In addition, postmortem studies (see below) have shown evidence of activated microglia with T-cells and B-cells in
grafted regions,19 raising the possibility that some de-
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gree of immune rejection may have contributed to the
lack of efficacy in these patients who received no immunosuppression, or only received cyclosporine for 6
months, and that patients might do better with more
prolonged immunosuppression.20 It is thus possible
that superior results might be attained with modifications in the transplant protocol.21 However, to date no
dopamine cell-based therapy has as yet been demonstrated to provide benefits for patients with PD in a
double-blind, controlled trial.
Transplant-Related Dyskinesias
Transplant procedures have generally been well tolerated. However, as many as 50% of transplantation patients develop a novel and previously unreported form
of involuntary movement referred to as “off-medication
dyskinesia.”4 – 6 Abnormal involuntary movements or
dyskinesias are a common complication of levodopa
therapy. Most often, they coincide with the peak levodopa plasma concentration and the period of maximal
clinical benefit, and disappear within 2 to 3 hours as
the levodopa dose wears off (peak-dose dyskinesia).
Less commonly, short-lasting (usually 5–10 minutes)
dyskinesias emerge in association with the rise and fall
of the plasma levodopa concentration following individual doses (diphasic dyskinesia). Graft-related dyskinesias have been described with similarities to peakdose dyskinesia5 and diphasic dyskinesias,4 but differ
from each of these in that they can persist for prolonged periods of time (days to weeks) after dose reduction or even complete withdrawal of levodopa; for
this reason, they have been referred to as “offmedication dyskinesia.”4 These involuntary movements
can be severe and disabling, and may necessitate an additional neurosurgical procedure (deep brain stimulation).5 The precise mechanism responsible for graftinduced dyskinesias is not known, but their presence
suggests that transplantation of dopamine cells using
current transplant protocols does not restore dopamine
in a physiological manner. At present, we lack an understanding of how to prevent off-medication dyskinesia and this side effect remains an obstacle to further
clinical testing of dopamine cell-based therapies in PD.
Neuropathologic Changes in Transplanted Dopamine
Cells
Initial neuropathologic studies performed 18 months
after the transplantation procedure demonstrated robust survival of healthy-appearing tyrosine hydroxylaseimmunoreactive (TH-ir) grafted dopamine neurons
with extensive reinnervation of the host striatum.2,3,17
However, approximately 11 to 14 years after the transplant procedure, grafted dopamine neurons were found
to contain inclusion bodies that stained positively for
alpha synuclein, ubiquitin, and thioflavin-S, and were
identical to Lewy bodies (Fig 1B).7–9 Graft sites did
not stain for dopamine transporter, and in more affected areas there was also reduced staining for tyrosine
hydroxylase. These findings are consistent with the
possibility that the implanted neurons had been adversely affected by the disease process. It thus appears
that following transplantation, even young, healthy, genetically independent dopamine cells can be affected
by the PD pathological process, which might limit
their ability to provide sustained benefit.
Nondopaminergic Features of PD
While most clinical and pathological attention in PD
has focused on the dopamine system, it is important to
appreciate that cell loss and Lewy body pathology can
also be seen in multiple other sites, including cholinergic, norepinephrine, and serotonin neurons in selected regions of the cerebral cortex, olfactory system,
basal forebrain, brain stem, spinal cord, and peripheral
autonomic nervous system.22 This nondopaminergic
pathology is thought to underlie clinical features such
as freezing, falling, autonomic dysfunction, mood disturbances, and dementia, which are not well controlled
with levodopa and represent the primary source of disability and nursing home placement for patients with
advanced PD.23 There is presently no data or scientific
basis to consider that transplantation of dopaminergic
cells into the striatum will relieve or modify these nondopaminergic features of the disease (Fig 2).24
Stem Cells and Gene Therapies
Stem cells have attracted considerable interest as a possible therapy for PD because of their potential to provide an unlimited supply of optimized dopamine neurons for transplantation.25 Numerous studies have
reported that dopamine neurons suitable for transplantation can be derived from mice, monkey, or human
embryonic stem cells, and that they can provide motor
benefits in rodent and nonhuman primate models of
PD.26 –28 Dopamine-producing cells can also be induced to differentiate from autologous stem cells generated from the umbilical matrix, bone marrow, and
reprogrammed fibroblasts.29 –32 Autologous stem cells
offer the advantage of avoiding the immunological and
societal concerns associated with the use of foreign embryonic tissue. To date, however, cell survival following
transplantation of dopamine neurons derived from
stem cells has been limited, and motor benefits in animal models do not exceed that which can be obtained
with fetal nigral cells, which have not as yet been
shown to provide benefits for PD patients in double
blind trials. The safety of stem cells has also not yet
been adequately assessed in preclinical studies. Specifically, tumor formation has been observed with transplanted embryonic stem cells in rodents26 and in a patient with ataxia telangiectasia who received a stem cell
transplant,33 and represents a major theoretical concern
for PD patients. Finally, there is no reason to believe
that dopaminergic stem cells will be any more likely to
address the nondopaminergic features of PD than
other dopaminergic therapies. While enthusiasm for
the potential of stem cells remains high, it is clear that
there are many issues that remain to be resolved before
clinical trials in PD patients can proceed, and there is
no assurance that this approach will prove to be superior to fetal nigral transplantation or more effective
than other available dopaminergic or surgical therapies.
Gene therapies offer a broad range of possibilities for
enhancing dopaminergic function, with the potential
of delivering proteins such as aromatic amino acid decarboxylase (AADC) that promote the conversion of
levodopa to dopamine34; glutamic acid decarboxylase
(GAD) that forms GABA and might suppress firing in
overactive glutamatergic neurons35; and trophic factors
such as neurturin or glial-derived neurotrophic factors
(GDNF) that might enhance survival and protect
against degeneration in targeted regions.36 While preliminary open-label studies have been promising with
each of these approaches, the only double-blind study
that has been performed to date showed no significant
benefit of adeno-associated virus type 2 (AAV2) delivery of neurturin in comparison to a sham procedure
(C.W.O., personal observations). In addition, each of
the studies that have been performed to date have targeted the nigrostriatal dopamine system or its connections, and it is not clear how these approaches would
Olanow et al: DA Cell-Based Therapy for PD
593
Fig 2. (A) Schematic representation of the normal nigrostriatal dopaminergic system (shown in red). Fibers from dopamine neurons
in the substantia nigra pars compacta project to the striatum (putamen and caudate nucleus). (B) Schematic representation of the
pattern of degeneration that occurs in Parkinson’s disease. Note that in addition to the degeneration in the nigrostriatal dopamine
system, there is degeneration in nondopaminergic regions, including the dorsal motor nucleus of the vagus (DMN), pedunculopontine nucleus (PPN), locus coeruleus (LC), nucleus basalis of Meynert (NBM), olfactory tract, and cerebral hemisphere. Degeneration
can also affect neurons in the spinal cord and peripheral autonomic nervous system (not shown). (C) Schematic representation of
dopaminergic graft deposits (black dots) transplanted into the striatum with dopaminergic reinnervation of the putamen and caudate nucleus (red areas). Note that it would not be anticipated, nor is there scientific data to suggest, that dopamine transplants
would reinnervate or restore function to areas of nondopaminergic neurodegeneration.
influence the important nondopaminergic features of
the disease.
Conclusions and Future Directions
What does all of this mean for the future of dopamine cell-based therapies in PD? We believe it is realistic to expect that with modifications in the transplant protocol, dopamine cell transplantation may
one day be able to restore striatal dopamine innervation in a physiological manner and provide clinical
benefits comparable to levodopa, but without motor
complications. However, we can already largely accomplish this goal with deep brain stimulation,37 and
it is very possible that we will soon be able to achieve
comparable results with medical therapies such as
long-acting formulations of levodopa.38 The more
important question is whether dopamine cell transplants can provide benefits that are superior to what
can be obtained with levodopa, and more specifically,
will they be able to provide benefits for the nondopaminergic features of the illness? At present there is
no data to indicate that this will be the case. It is
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theoretically possible that physiologic restoration of
the nigrostriatal dopamine system could have consequences that extend to nondopaminergic neurons.
For example, physiologic restoration of dopamine
could inhibit overactivity in neurons of the subthalamic nucleus, and thereby prevent glutamate-mediated
excitotoxic damage in its targeted nondopaminergic
structures.39 Transplantation into alternate targets such
as the substantia nigra pars compacta might physiologically restore dopamine innervation to extrastriatal regions and thereby improve deficits related to cortical
and brain stem dopamine deficiency that might not
benefit from traditional levodopa therapy. It is also
possible that transplantation of different cell types (eg,
glia), or the use of implanted cells to deliver molecules
such as trophic factors or proteins that are deficient or
exist in a mutant form in hereditary forms of PD (eg,
Parkin) might provide more widespread benefits than
are currently contemplated. Indeed, it is possible that
certain selected patient subtypes manifesting a pure nigrostriatal dopamine deficiency, such as patients with
early-onset autosomal recessive PD, might remain ex-
cellent candidates for a dopamine cell transplant. However, all of these concepts are theoretical and presently
lack empirical confirmation.
In summary, cell-based dopaminergic therapies using
current transplant designs have not as yet met expectations. The failure of dopaminergic cell-based therapies
to achieve efficacy in double blind clinical trials, the
development of unanticipated and occasionally disabling side effects, evidence that implanted cells themselves can develop the pathological changes of PD, and
the likelihood that these treatments will not address the
nondopaminergic features of the disease do not bode
well for the near-term future of cell-based therapies as a
clinically meaningful treatment for the majority of patients with PD. For the present, it would seem that
greater opportunities for more effective therapies in PD
would derive from better understanding of the etiology
and pathogenesis of the disease and the development of
neuroprotective therapies that might slow or stop disease progression.
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