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PERSPECTIVES
OPINION
Cell therapy in Parkinson’s disease –
stop or go?
Stephen B. Dunnett, Anders Björklund and Olle Lindvall
The results of the first double-blind placebocontrolled trial using grafts of embryonic
tissue to treat Parkinson’s disease have
aroused widespread interest and debate
about the future of cell replacement
therapies. What are the key issues that need
to be resolved and the directions in which
this technology is likely to develop?
The recent publication in The New England
Journal of Medicine of the first double-blind
placebo-controlled trial of embryonic tissue
transplantation in Parkinson’s disease (PD)1
has stimulated widespread media interest
and scientific debate about the whole future
of cell replacement therapies2. Whereas some
of the concerns might have been overplayed3,
it is appropriate to review the current status
of clinical trials of cell-based therapies for PD
in the context of the historical development
of the field. We consider here the key issues
still to be resolved and the directions in
which this technology is likely to develop in
the near future.
Cell-based therapies for PD have been
developed over the past three decades
(TIMELINE) within a relatively simple conceptual framework: if the human disease is
attributable to a primary degeneration of the
dopamine neurons of the substantia nigra
and a corresponding loss of dopamine
innervation of the neostriatum (caudate
nucleus and putamen), then replacement of
the lost dopamine neurons by transplantation should yield recovery of the associated
motor symptoms. As we learn more, not just
about whether but also about how grafts
exert their functional effects, it becomes
apparent that effective therapies can only be
developed hand-in-hand with acquiring a
rational understanding of the neurobiological principles that underlie the integration
and function of grafted cells in the damaged
nervous system.
Successful transplantation of catecholamine-secreting cells in the nervous system was first achieved by Olson and colleagues in the early 1970s by grafting adrenal
chromaffin cells or embryonic dopamine
neurons into the rat anterior eye chamber4,5.
These studies established that survival, neurite outgrowth and formation of contacts
with the host nervous system are best achieved
using developing embryonic neurons. The
dopaminergic fate of the implanted cells is
determined before implantation and depends
on accurate dissection of the relevant ventral
mesencephalic cell groups from embryos
harvested during a critical stage of development6. Initial attempts to transplant embryonic neurons into the adult brain proved
more difficult and required rather complex
technical protocols to provide adequate
nutrient support for newly grafted tissue
pieces7. However, these limitations were
largely overcome with the development of
techniques for preparation of dissociated cell
suspensions, allowing stereotactic implantation of embryonic dopamine neurons directly
into deep brain sites8.
The first reports of functional recovery in
simple tests of motor asymmetry in hemi-
NATURE REVIEWS | NEUROSCIENCE
parkinsonian rats were based on solid graft
implants into the lateral ventricles9 or cortical cavities10,11. However, this was soon replicated using the then new cell-suspension
technology, revealing the importance of
topographic placement and terminal reinnervation in determining functional efficacy
of the grafted cells12,13. At the technical level,
subsequent experimental studies have identified treatments for cool storage (‘hibernation’) of donor tissues14, refinements in the
methods of cell preparation and implantation15, and improved trophic/neuroprotective support of grafted tissues16. Further
behavioural analysis has demonstrated
recovery in a range of more complex motor
functions17 and extended functional validation to primates18,19. In parallel, a combination of electrophysiological, in vivo neurochemistry and behavioural analyses have
provided a clearer understanding of the
mechanisms of graft function20. It is not simply sufficient for the grafted cells to secrete
dopamine at physiological levels into the
host neuropil; rather, full functional activity
is dependent on a synaptic integration of the
grafted cells into the host neural circuitry.
Open-label clinical trials
The first clinical trials of cell transplantation
in PD used adrenal autografts21. In this procedure, one adrenal medulla of the person with
PD is removed for dissection of the relevant
cells, and implanted back into the brain,
either as solid pieces into a ventricular cavity
or by stereotaxic injections of cell suspensions
into the striatal neuropil. Following a single
report of an apparently profound effect22, several hundred patients received this operation
in the late 1980s in a series of rather poorly
controlled trials worldwide. However, it soon
became apparent that the grafts did not survive long-term and that, at best, modest clinical effects were accompanied by significant
side effects and an unacceptable level of morbidity and mortality23. This procedure, therefore, is generally not considered to offer an
acceptable option.
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PERSPECTIVES
Timeline | A brief history of cell therapies for Parkinson’s disease
Successful
transplantation of
adrenal medulla and
fetal nigral cells in
the anterior eye
chamber4,5.
1970–1972
1976
First published
report of functional
nigral grafts in
hemiparkinsonian
rats9,10.
1979
Successful
transplantation of
fetal nigral cells in
the rat brain7.
Functional recovery
by nigral grafts in a
range of behavioural
tests (dependent on
placement and extent
of reinnervation)54–56.
1980
Introduction of the
cell-suspension
transplantation
method in rats8.
The alternative was to pursue a clinical
strategy based on that which works best in
experimental model systems, namely human
embryonic tissue allografts. The complex ethical and legal issues associated with the use of
human embryonic tissues from elective abortions have now been considered in detail in
most western countries, resulting in approved
guidelines that permit use of embryonic tissues subject to stringent conditions for selection, consent, collection, handling and application24. The first patients to receive human
embryonic nigral grafts, in Sweden and
Mexico, had only very limited benefit25,26.
However, subsequent improvements in technique have resulted in clear-cut and long-lasting symptomatic improvement (in the order
of 30–50% on the the motor examination
part of the unified Parkinson’s disease rating
scale) as reported in open-label trials from
several centres around the world (TABLE 1).
The issue of how to determine whether a
novel surgical treatment in PD is having significant benefit is not straightforward. PD is a
slowly progressive disorder and symptoms
can fluctuate markedly depending on time of
day and position in the drug cycle, as well as
being sensitive to mood and motivation.
Placebo effects are well known. Moreover,
transplanted cells require many months to
develop and integrate into the host nervous
system and the grafts cannot easily be
removed (other than as a result of graft failure
or rejection), so an experimental design for
testing patients reversibly on and off treatment is not feasible. Finally, at this stage of
their development, we consider that graft
technologies are not yet optimized and so
need to be refined and developed on a caseby-case basis. Consequently, most centres have
adopted the strategy of undertaking detailed
366
1981
First published report of
fetal nigral grafts in
patients with Parkinson’s
disease (operations in
1987)25,26,57.
1985
First published report
of adrenal medulla
grafts in patients with
Parkinson’s disease
(operations in 1982) 21.
1988
1990
First post-mortem
evidence of nigral graft
survival in patients with
Parkinson’s disease42.
1995
First evidence of nigral
graft survival and
functional recovery in
patients with
Parkinson’s disease30.
First report of surviving
nigral xenografts in a
patient with
Parkinson’s disease
(operations in 1994)46.
longitudinal analysis of individual cases under
defined conditions of drug administration. A
consortium of European and US centres has
developed a standardized Core Assessment
Protocol for Intracerebral Transplantations
(CAPIT), which defines regular neurological
and imaging assessments at defined time
intervals to provide an extended baseline over
a minimum of three months pre-operation
and one to two years post-operation27,28.
Adoption of the CAPIT protocol provides two
distinct advantages: it allows data to be pooled
from several centres to provide large sample
sizes even when each contributing centre
might study only a few cases, and it allows
direct comparison between different tissue
preparations and surgical methods used in different centres according to a common set of
baseline and outcome assessments28.
“It is only through the study
of a progressively modified
technology in small
numbers of patients using
standardized, well-validated
assessment protocols that
we can determine whether
the refinements identified
experimentally translate
into clinical benefit.”
On the basis of such open-label longitudinal analysis of small numbers of cases using
defined assessment protocols, there is now
clear evidence of both clinical benefit and graft
| MAY 2001 | VOLUME 2
1997
Positron-emission tomography
(PET) evidence of regulated
dopamine release from nigral
grafts in a patient with
Parkinson’s disease37.
1999
2000
PET evidence of graftinduced restoration of
movement-related cortical
activation in patients with
Parkinson’s disease48.
survival after embryonic tissue transplantation (TABLE 1). This can be illustrated from the
series of 18 patients studied in Lund, with collaborators in London and Munich/Marburg29.
These patients have been followed longitudinally for up to ten years; the substantial
majority show significant increases in the proportion of time spent in the ‘on’ phase (that is,
with few or no motor symptoms), improvements in the speed and accuracy of movements (as observed, for example, in timed
series of pronation/supination) in defined
‘off ’ (that is, after drug withdrawal), and
maintenance of the improvement with progressive reduction (or complete cessation in
several cases) of concurrent L-DOPA (3,4dihydroxyphenylalanine) treatment30–35. In
parallel with the neurological testing, the
patients have received regular [18F]-DOPA
positron-emission tomography (PET) scans
in which [18F]-DOPA uptake, as measured by
the Ki uptake constant, is seen to return
towards normal levels30–37. However, in this
and other patient series operated with the current transplantation procedure, [18F]-DOPA
uptake in the putamen has reached only
48–68% of that measured in healthy volunteers (TABLE 1), with the exception of one
patient with a unilateral graft where restitution was seen to reach 100% (REF. 37), indicating that there is room for considerable
improvement. The step-by-step approach
adopted in these studies has made it possible
to introduce, for example, modifications in
the surgical technique38, and improvements in
storage and preparation of the tissue34. We are
confident that this stepwise approach has
been successful in yielding significant refinements in methodology without the risk of
affecting large numbers of patients with a
poor or ill-conceived technique.
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PERSPECTIVES
Table 1 | Functional outcome after bilateral intrastriatal nigral grafts in clinical trials*
Surgical Trial
centre
design
No. of
cases
No. of ventral
mesencephalon
per putamen
Graft
placement
[18F]-DOPA uptake
(%increase/
%normal)
UPDRS
motor score
(% change)
L-DOPA
Time
in ‘off’
doses
(% change#)(% change#)
Lund‡
OL
OL
OL
4
2
5
4.9
2.5
2.8 (+L)
Put
C + Put
C + Put
60/52
87/68
55/48
–30
–50 (total)
–40
–59
–50, NR
–43
–37
0, –70
–45
Tampa
OL
6
3.0–4.0
P Put
61/55
–30
–43
–16
49
Créteil
OL
3
6
1.0–1.5
3.0
Put
NR§
–6
–33
15
–66
NR
50
Halifax
OL
2
3.25 (+G)
P Put
107/62
–32 (total)
–50
NR
51
NR
No change
Denver
DBPC
19
2.0
Put
40/NR
–18
||
References
33
35
34,48
1
*Trials involved objective longitudinal assessment protocols and had positron-emission tomography evidence of graft survival.
‡
The Lund series also comprises three patients that have received only unilateral transplants 26,37 and one patient with possible multiple-system atrophy 32,33. Three
patients have not yet been reported.
§
Five patients in the Créteil series showed 60% increase in striatal [18F]-dopa uptake, reaching 37% of the normal mean after unilateral grafting of tissue from 1–3 donors
in Put (n=1) or C + Put (n=4) 52,53.
||
–34% in the younger patients (≤60 years old).
#
Negative scores indicate reductions, that is improvements, in response.
(C, caudate nucleus; DBPC, double-blind placebo-controlled; DOPA; 3,4-dihydroxyphenylalanine; +G, with glial cell-line-derived neurotrophic factor; +L, with lazaroids;
NR, not reported; OL, open-label; P, posterior; Put, putamen; UPDRS, unified Parkinson’s disease rating score.)
Denver/New York trial
The recent Denver/New York surgical trial1 is
distinctive for providing the first published
double-blind placebo-controlled trial of
neural transplantation in PD. Although such
a design is considered necessary by some to
provide unequivocal scientific evidence of
efficacy of any treatment modality39, there are
significant ethical problems associated with
using sham procedures in surgical trials40.
Three other surprising features of the design
of this trial were: clinical assessment was not
conducted according to established CAPIT
protocols (which would have allowed comparability with other studies); assessments were
only undertaken up to one year after grafting
(which would maximize placebo effects but
which is likely to be too early to assess the
level of slowly developing graft-induced therapeutic benefit); and the selection of patients’
retrospective global self-assessment as the
primary outcome measure (which showed
considerable variation but no difference
between placebo and control groups).
Moreover , the technique for cell transplantation in this trial differed from most other
studies in the number of embryonic donors,
methods of cell preparation and long-term
storage, absence of immunosuppression and
the use of an unconventional surgical
approach, so that it was unclear from the outset whether this controlled trial would in fact
be informative41. Nevertheless, even at the
early one-year time point, modest but significant improvement was obtained in two neurological rating scales, in particular in young
patients. There was no improvement in the
sham-operated group. This was accompanied
by a 40% increase in [18F]-DOPA uptake, and
survival of 7,000–40,000 tyrosine-hydroxylase-positive (presumed dopamine) cells per
side in two post-mortem cases (compared
with 80,000–135,000 cells per side using conventional methods in other post-mortem
analyses42). As such, the outcome using this
distinctive surgical approach follows that seen
in the open label trials, with a level of functional benefit commensurate with the modest
survival of the grafts obtained (TABLE 1).
However, what has attracted widespread
attention about this trial has been the reports
of severe and uncontrollable dyskinetic side
effects after 1–3 years in 5 of 33 patients in the
trial. This has been taken in various media
reports as a serious blow to the acceptability
of dopamine neuron transplantation per se2.
However, it should be noted that side effects
of the dramatic severity reported from the
Denver/New York trial have not been evident
in the open-label trials, and amelioration
rather than induction of dyskinesias has been
observed after dopamine neuron transplantation in animal models of PD43. We believe
that once the reported dyskinesias are properly characterized, they might be found to be
attributable to one or several features of the
particular protocol used in this trial — in particular, the use of tissue stored in culture for
up to four weeks before grafting and the
unconventional surgical approach using needle trajectories passing through the frontal
lobes, and perhaps also the lack of any
immunosuppressive treatment — rather than
being a general feature of dopamine-cell
replacement using experimentally validated
methods. Freed et al.1 have suggested that the
late-appearing dyskinesias observed in the
Denver/New York trial might be due to a
dopamine overdose effect in their grafted
patients. However, the low dopamine neuronal survival observed in their study clearly
argues against this possibility. Furthermore,
NATURE REVIEWS | NEUROSCIENCE
the most successfully treated person reported so far, in whom the grafts had restored
dopamine storage and release in the striatum to normal levels37, has not developed
any significant dyskinesias.
What do we still need to know?
With the development of new effective treatments for patients with advanced PD, in particular deep-brain stimulation, it is necessary
to ask whether it is justified to make any further efforts to develop cell-based therapies
for this disorder. We would argue that cell
therapy, if successful, offers several unique
features and distinctive advantages over
other treatment strategies. Cell therapy aims
to restore dopamine transmission in the
striatum, that is, in the precise area that has
lost its intrinsic dopamine afferent innervation. In successful cases, this has given major
clinical improvements and allowed the
patient to stop L-DOPA medication, without
major side effects. The grafted neurons are
not destroyed by the disease process up to at
least ten years after surgery, indicating that
the symptomatic relief can be maintained for
many years31–33,37.
The further development of the cell
replacement approach, however, is severely
hampered by the lack of well-characterized,
standardized and quality-controlled cell
material. As long as neural transplantation
has to rely on the access to embryonic donor
tissue, widespread application will always be
limited. For this reason, the past decade has
seen an active search for alternative sources
of cells for therapeutic application44. The
main alternatives under active investigation
are xenografts, stem cells and other genetically
manipulated or immortalized cells and cell
lines. Each has significant advantages over
VOLUME 2 | MAY 2001 | 3 6 7
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PERSPECTIVES
primary embryonic cells in the prospects of
providing regular supplies of large numbers
of cells, availability on demand and options
for standardized preparation protocols to
enhance reproducibility, quality and safety.
Moreover, there is good experimental evidence that, under certain conditions, each
can provide functionally effective dopamine
replacement in the striatum45. Nevertheless,
there remain significant hurdles to overcome: effective immunosuppression and
safety from zoonoses in the case of
xenografts, and controlled differentiation
into neurons that develop and connect with a
mature dopamine phenotype in the case of
stem cells and other cell lines. In our judgement, none of these approaches is yet developed to the stage of being ready for clinical
application, notwithstanding a first clinical
study using porcine embryonic mesencephalic tissue in which graft survival was
poor and functional benefit very modest46,47.
Whatever the hopes of long-term alternatives, primary embryonic cells remain the
one effective source for clinical transplantation at this stage of development of the field,
and they remain the gold standard for efficacy against which other cell types need to be
compared, not only in experimental models
but ultimately in the clinic.
Although much refined since the first surgical trials were started 15 years ago, the present protocols for primary embryonic cell
preparation and transplantation are not yet
optimal, and further improvement is almost
certainly achievable. For example, refinements in tissue protocols to provide more
effective neuroprotection both in vitro and
after transplantation — by a combination of
antioxidant, anti-excitotoxic, anti-apoptotic
and trophic strategies — can be expected to
provide higher dopamine cell survival16. On
the surgical side, at present, grafts are
implanted in a standard set of placements,
mostly in the putamen alone. We clearly need
to acquire a better understanding of the
topography of striatal function as it relates to
the pattern of disease symptoms in people
with PD. This should be combined with
improved resolution of diagnostic imaging to
provide selective targeting of graft placements
tailored to the distribution of dopaminergic
denervation and the profile of symptoms in
the individual patient.
Do we need further clinical trials now? It
is only through the study of a progressively
modified technology in small numbers of
patients using standardized, well-validated
assessment protocols that we can determine
whether the refinements identified experimentally translate into clinical benefit. It is
368
argued by others that we can only be confident that the effects seen are not simply
attributable to placebo effects by undertaking
double-blind trials involving control patients
receiving sham operations39. However, the
large number of cases in which suboptimal
grafting techniques yield relatively poor
graft survival and at best modest clinical
benefit, alongside the sham-operated patients
in the Denver/New York trial1, already provide a substantial body of relevant surgical
control data. The time for a full-scale double-blind surgical-controlled trial will come
when the grafting methods approach optimization. At such time, neural transplantation should be properly compared against
the best surgical alternatives (such as subthalamic stimulation) rather than against
sham-operated controls. However, in our
judgement, that level of optimization is not
yet achieved, and the time and effort
required for undertaking such a trial at this
stage would simply slow steady progress in
surgical refinements.
Stephen B. Dunnett is at the School of Biosciences,
Cardiff University, Cardiff CF10 3US, Wales.
Anders Björklund and Olle Lindvall are at the
Wallenberg Neuroscience Center, Lund University,
221 84 Lund, Sweden.
Correspondence to S.B.D.
e-mail: [email protected]
Links
FURTHER INFORMATION Virtual hospital:
functional anatomy of the basal ganglia
ENCYCLOPEDIA OF LIFE SCIENCES Parkinson
disease
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
MIT ENCYCLOPEDIA OF COGNITIVE SCIENCE
Basal ganglia
23.
1.
24.
2.
3.
4.
5.
6.
7.
8.
9.
Freed, C. R. et al. Transplantation of embryonic dopamine
neurons for severe Parkinson’s disease. N. Engl. J. Med.
344, 710–719 (2001).
Kolata, G. Parkinson’s disease is set back by failure of
fetal cell implants. NY Times 8 March, 381 (2001).
Editorial. Prospects for Parkinson’s disease. Nature Med.
7, 381 (2001).
Olson, L. & Malmfors, T. Growth characteristics of
adrenergic nerves in the adult rat. Fluorescence
histochemical and 3H-noradrenaline uptake studies using
tissue transplantation to the anterior chamber of the eye.
Acta Physiol. Scand. 348, S1–S112 (1970).
Olson, L. & Seiger, Å. Brain tissue transplanted to the
anterior chamber of the eye. I. Fluorescence
histochemistry of immature catecholamine and
5-hydroxytryptamine neurons innervating the iris.
Z. Zellforsch. 195, 175–194 (1972).
Olson, L., Seiger, Å. & Strömberg, I. Intraocular
transplantation in rodents: a detailed account of the
procedure and examples of its use in neurobiology with
special reference to brain tissue grafting. Adv. Cell.
Neurobiol. 4, 407–442 (1983).
Stenevi, U., Björklund, A. & Svendgaard, N.-A.
Transplantation of central and peripheral monoamine
neurons to the adult rat brain: techniques and conditions
for survival. Brain Res. 114, 1–20 (1976).
Björklund, A., Schmidt, R. H. & Stenevi, U. Functional
reinnervation of the neostriatum in the adult rat by use of
intraparenchymal grafting of dissociated cell suspensions
from the substantia nigra. Cell Tissue Res. 212, 39–45
(1980).
Perlow, M. J. et al. Brain grafts reduce motor
| MAY 2001 | VOLUME 2
25.
26.
27.
28.
29.
30.
31.
32.
abnormalities produced by destruction of nigrostriatal
dopamine system. Science 204, 643–647 (1979).
Björklund, A. & Stenevi, U. Reconstruction of the
nigrostriatal dopamine pathway by intracerebral
transplants. Brain Res. 177, 555–560 (1979).
Björklund, A., Dunnett, S. B., Stenevi, U., Lewis, M. E. &
Iversen, S. D. Reinnervation of the denervated striatum
by substantia nigra transplants: functional consequences
as revealed by pharmacological and sensorimotor
testing. Brain Res. 199, 307–333 (1980).
Dunnett, S. B., Björklund, A., Schmidt, R. H., Stenevi,
U. & Iversen, S. D. Intracerebral grafting of neuronal cell
suspensions. V. Behavioral recovery in rats with bilateral
6-OHDA lesions following implantation of nigral cell
suspensions. Acta Physiol. Scand. 522, S39–S47
(1983).
Schmidt, R. H., Björklund, A., Stenevi, U., Dunnett, S. B.
& Gage, F. H. Intracerebral grafting of neuronal cell
suspensions. III. Activity of intrastriatal nigral suspension
implants as assessed by measurements of dopamine
synthesis and metabolism. Acta Physiol. Scand. 522,
S19–S28 (1983).
Sauer, H. & Brundin, P. Effects of cool storage on survival
and function of intrastriatal ventral mesencephalic grafts.
Rest. Neurol. Neurosci. 2, 123–135 (1991).
Nikkhah, G. et al. A microtransplantation approach for
cell suspension grafting in the rat Parkinson model: A
detailed account of the methodology. Neuroscience 63,
57–72 (1994).
Brundin, P. et al. Improving the survival of grafted
dopaminergic neurons: a review over current
approaches. Cell Transplant. 9, 179–195 (2000).
Winkler, C., Kirik, D., Björklund, A. & Dunnett, S. B.
Transplantation in the rat model of Parkinson’s disease:
ectopic versus homotopic graft placement. Prog. Brain
Res. 127, 233–265 (2000).
Taylor, J. R. et al. Grafting of fetal substantia nigra to
striatum reverses behavioral deficits induced by MPTP in
primates: a comparison with other types of grafts as
controls. Exp. Brain Res. 85, 335–348 (1991).
Annett, L. E., Torres, E. M., Ridley, R. M., Baker, H. F. &
Dunnett, S. B. A comparison of the behavioural effects of
embryonic nigral grafts in the caudate nucleus and in the
putamen of marmosets with unilateral 6-OHDA lesions.
Exp. Brain Res. 103, 355–371 (1995).
Dunnett, S. B. & Björklund, A. in Functional Neural
Transplantation (eds Dunnett, S. B. & Björklund, P.)
531–567 (Raven, New York, 1994).
Backlund, E. O. et al. Transplantation of adrenal medullary
tissue to striatum in parkinsonism. J. Neurosurg. 62,
169–173 (1985).
Madrazo, I. et al. Open microsurgical autograft of adrenal
medulla to the right caudate nucleus in two patients with
intractable Parkinson’s disease. N. Engl. J. Med. 316,
831–834 (1987).
Quinn, N. P. The clinical application of cell grafting
techniques in patients with Parkinson’s disease. Prog.
Brain Res. 82, 619–625 (1990).
Boer, G. J. Ethical guidelines for the use of human
embryonic or fetal tissue for experimental and clinical
neurotransplantation and research. J. Neurol. 242, 1–13
(1994).
Madrazo, I. et al. Transplantation of fetal substantia nigra
and adrenal medulla to the caudate nucleus in two
patients with Parkinson’s disease. N. Engl. J. Med. 318,
51 (1988).
Lindvall, O. et al. Human fetal dopamine neurons
grafted into the striatum in 2 patients with severe
Parkinson’s disease: a detailed account of methodology
and a 6-month follow-up. Arch. Neurol. 46, 615–631
(1989).
Langston, J. W., Widner, H. & Goetz, C. G. Core
assessment program for intracerebral transplantation
(CAPIT). Mov. Disord. 7, 2–13 (1992).
Defer, G. L., Widner, H., Marié, R. M., Rémy, P. &
Levivier, M. Core assessment program for surgical
interventional therapies in Parkinson’s disease (CAPSITPD). Mov. Disord. 14, 572–584 (1999).
Lindvall, O. & Hagell, P. Clinical observations after neural
transplantation in Parkinson’s disease. Prog. Brain Res.
127, 299–320 (2000).
Lindvall, O. et al. Grafts of fetal dopamine neurons
survive and improve motor function in Parkinson’s
disease. Science 247, 574–577 (1990).
Lindvall, O. et al. Evidence for long-term survival and
function of dopaminergic grafts in progressive
Parkinson’s disease. Ann. Neurol. 35, 172–180 (1994).
Wenning, G. K. et al. Short- and long-term survival and
function of unilateral intrastriatal dopaminergic grafts in
Parkinson’s disease. Ann. Neurol. 42, 95–107 (1997).
www.nature.com/reviews/neuro
© 2001 Macmillan Magazines Ltd
PERSPECTIVES
33. Hagell, P. et al. Sequential bilateral transplantation in
Parkinson’s disease — effects of the second graft. Brain
122, 1121–1132 (1999).
34. Brundin, P. et al. Bilateral caudate and putamen
grafts of embryonic mesencephalic tissue treated with
lazaroids in Parkinson’s disease. Brain 123, 1380–1390
(2000).
35. Widner, H. et al. Bilateral fetal mesencephalic grafting in 2
patients with parkinsonism induced by 1-methyl-4phenyl-1,2,3,6- tetrahydropyridine (MPTP). N. Engl. J.
Med. 327, 1556–1563 (1992).
36. Sawle, G. V. et al. Transplantation of fetal dopamine
neurons in Parkinson’s disease: PET [F-18] 6-Lfluorodopa studies in 2 patients with putaminal implants.
Ann. Neurol. 31, 166–173 (1992).
37. Piccini, P. et al. Dopamine release from nigral transplants
visualised in vivo in a Parkinson’s patient. Nature
Neurosci. 2, 1137–1140 (1999).
38. Brundin, P. in Neural Transplantation: A Practical Approach
Transplantation (eds Dunnett, S. B. & Björklund, P.)
139–160 (IRL, Oxford, 1992).
39. Freeman, T. B. et al. Use of placebo surgery in controlled
trials of a cellular-based therapy for Parkinson’s disease.
N. Engl. J. Med. 341, 988–992 (1999).
40. Macklin, R. Placebo surgery in trials of therapy for
Parkinson’s disease. Reply. N. Engl. J. Med. 342, 355
(2000).
41. Widner, H. et al. NIH neural transplantation funding.
Science 263, 737 (1994).
42. Kordower, J. H. et al. Neuropathological evidence of graft
survival and striatal reinnervation after the transplantation
of fetal mesencephalic tissue in a patient with Parkinson’s
disease. N. Engl. J. Med. 332, 1118–1124 (1995).
43. Lee, C. S., Cenci, M. A., Schulzer, M. & Björklund, A.
Embryonic ventral mesencephalic grafts improve
levodopa-induced dyskinesia in a rat model of
Parkinson’s disease. Brain 123, 1365–1379 (2000).
44. Dunnett, S. B. & Björklund, A. Parkinson’s disease:
prospects for novel restorative and neuroprotective
treatments. Nature 399, S32–S39 (1999).
45. Dunnett, S. B. et al. in Neurochemistry Transplantation
(eds Teelken, A. W. & Korf, J.) 249–257 (Plenum, New
York, 1997).
46. Deacon, T. et al. Histological evidence of fetal pig neural
cell survival after transplantation into a patient with
Parkinson’s disease. Nature Med. 3, 350–353 (1997).
47. Schumacher, J. M. et al. Transplantation of embryonic
porcine mesencephalic tissue in patients with PD.
Neurology 54, 1042–1050 (2000).
48. Piccini, P. et al. Delayed recovery of movement-related
cortical function in Parkinson’s disease after striatal
dopaminergic grafts. Ann. Neurol. 48, 689–695 (2000).
49. Hauser, R. A. et al. Long-term evaluation of bilateral fetal
nigral transplantation in Parkinson disease. Arch. Neurol.
56, 179–187 (1999).
50. Nguyen, J. P. et al. Bilateral intrastriatal grafts of fetal
mesencephalic neurons in Parkinson’s disease: long-term
results in 9 patients. Mov. Disord. 15, S53–S54 (2000).
51. Mendez, I. et al. Enhancement of survival of stored
dopaminergic cells and promotion of graft survival by
exposure of human fetal nigral tissue to glial cell linederived neurotrophic factor in patients with Parkinson’s
disease — report of two cases and technical
considerations. J. Neurosurg. 92, 863–869 (2000).
52. Defer, G. L. et al. Long-term outcome of unilaterally
transplanted Parkinsonian patients. 1. Clinical approach.
Brain 119, 41–50 (1996).
53. Rémy, P. et al. Clinical correlates of [18F]fluorodopa uptake
in five grafted Parkinsonian patients. Ann. Neurol. 38,
580–588 (1995).
54. Dunnett, S. B., Björklund, A., Stenevi, U. & Iversen, S. D.
Behavioral recovery following transplantation of
substantia nigra in rats subjected to 6-OHDA lesions of
the nigrostriatal pathway. 2. Bilateral lesions. Brain Res.
229, 457–470 (1981).
55. Dunnett, S. B., Björklund, A., Stenevi, U. & Iversen, S. D.
Grafts of embryonic substantia nigra reinnervating the
ventrolateral striatum ameliorate sensorimotor impairments
and akinesia in rats with 6-OHDA lesions of the
nigrostriatal pathway. Brain Res. 229, 209–217 (1981).
56. Dunnett, S. B., Björklund, A., Stenevi, U. & Iversen, S. D.
Behavioral recovery following transplantation of
substantia nigra in rats subjected to 6-OHDA lesions of
the nigrostriatal pathway. 1. Unilateral lesions. Brain Res.
215, 147–161 (1981).
57. Lindvall, O. et al. Fetal dopamine-rich mesencephalic
grafts in Parkinson’s disease. Lancet 2, 1483–1484
(1988).
Instructions concerning a dislocation of a vertebra in the neck. “If you examine a man with a neck injury …
and find he is without sensation in both arms and both legs, and unable to move them, and he is incontinent of
urine … it is due to the breaking of the spinal cord caused by dislocation of a cervical vertebra. This is a condition
which cannot be treated.” Edwin Smith Surgical Papyrus, Case 31. Thebes, c. 1550 BC. Taken from Breasted, J. H.
(ed.) The Edwin Smith Surgical Papyrus © The University of Chicago Press, 1930.
OPINION
Olfactory ensheathing cells — another
miracle cure for spinal cord injury?
Geoff Raisman
Several recent publications describe
remarkably promising effects of
transplanting olfactory ensheathing cells as
a potential future method to repair human
spinal cord injuries. But why were cells
from the nose transplanted into the spinal
cord? What are olfactory ensheathing
cells, and how might they produce these
beneficial effects? And more generally,
what do we mean by spinal cord injury? To
what extent can we compare repair in an
animal to repair in a human?
Nerve cells in the brain and spinal cord communicate with each other by means of myelinated axonal processes, which can be up to a
metre or more in length, and which travel
through pathways, called white matter tracts,
to reach their destinations. The white matter
tracts consist of a highly organized cellular
substrate, made up of several types of glial cell
(astrocytes, oligodendrocytes, which produce
myelin, and microglia). The glial cells are far
greater in number than the nerve cells, and
NATURE REVIEWS | NEUROSCIENCE
are woven into a complex tapestry of almost
crystalline regularity1. During development,
the progressive assembly of this glial cell array
provides cues that are essential for the nerve
fibres to find their correct pathways2.
The nervous system is subject to two
unique types of injury: one (typified by
spinal cord injury and strokes affecting fibre
pathways) in which the axons are severed
(axotomy), and another (typified by multiple
sclerosis) in which the axons lose their
myelin sheaths. Axotomy leads to the disconnection of nerve cells. Demyelination impairs
conduction. Both result in loss of function.
After axotomy in the adult central nervous system (CNS), the cut ends of the axons
sprout, but the sprouts are unable to grow
back along their original pathways, and the
functional loss is permanent. The injury also
damages the glial cells and disrupts the regularly aligned glial array of the white matter.
The response of the glial cells to damage leads
to death of oligodendrocytes3,4, changes the
anatomical arrangement of astrocytes (often
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