Here is a summary of published reports
(as of the end of 1994)
on fetal transplants in response to sheila's query.
It is also posted at
http://neurosurgery.mgh.harvard.edu/oisacson.htm
for those with web access.
Alan Bonanders well-informed recent posting to the
list on this topic is also worth consulting as
a thoughtful counterpoint to these references
(which are presented in answer to
the query without any implied endorsement--
although the Swedish reports represent the
results of a long and comprehensive
research program that continues there).
 
(They are current as of the end of 1994)
 
 
 
AN 95089583
AU Kupsch A. Oertel WH.
IN Klinikum Grosshadern, Neurological Unit,
Ludwig-Maximilians-University, Munchen, FRG.
TI Neural transplantation, trophic factors and
Parkinson's disease. [Review] SO Life Sciences.
55(25-26):2083-95, 1994.
AB Part 1 of this update on new restorative
therapeutic strategies against Parkinsons's disease
focuses on transplantation of dopamine-secreting
tissue. Special emphasis is put on clinical trials
with fetal mesencephalic cells. Problems and
potential alternative approaches are discussed.
Part 2 emphasizes progress in the related field of
neurotrophic factors for dopaminergic midbrain
neurons. [References: 78]
 
AN 95066035
AU Aminoff MJ.
IN Department of Neurology, University of
California, San Francisco, School of Medicine
94143-0114.
TI Treatment of Parkinson's disease. [Review]
SO Western Journal of Medicine. 161(3):303-8,
1994 Sep.
AB Pharmacotherapy with levodopa for
Parkinson's disease provides symptomatic benefit,
but fluctuations in (or loss of) response may
eventually occur. Dopamine agonists are also
helpful and, when taken with low doses of
levodopa, often provide sustained benefit with
fewer side effects; novel agonists and new methods
for their administration are therefore under study.
Other therapeutic strategies are being explored,
including the use of type B monoamine oxidase
inhibitors to reduce the metabolic breakdown of
dopamine, catechol-O-methyltransferase
inhibitors to retard the breakdown of levodopa,
norepinephrine precursors to compensate for
deficiency of this neurotransmitter, glutamate
antagonists to counteract the effects of the
subthalamic nucleus, and various neurotrophic
factors to influence dopaminergic nigrostriatal
cells. Surgical procedures involving pallidotomy
are sometimes helpful. Those involving cerebral
transplantation of adrenal medullary or fetal
mesencephalic tissue have yielded mixed results;
benefits may relate to the presence of growth
factors in the transplanted tissue. The
transplantation of genetically engineered cell lines
will probably become the optimal transplantation
procedure. The cause of Parkinson's disease may
relate to oxidant stress and the generation of free
radicals. It is not clear whether treatment with
selegiline hydrochloride (a type B monoamine
oxidase inhibitor) delays the progression of
Parkinson's disease, because the drug also exerts a
mild symptomatic effect. Daily treatment with
vitamin E (a scavenger of free radicals) does not
influence disease progression, perhaps because of
limited penetration into the brain. [References:
57]
 
AN 95007800
AU Koutouzis TK. Emerich DF. Borlongan CV.
Freeman TB. Cahill DW. Sanberg PR.
IN Department of Surgery, University of South
Florida College of Medicine, Tampa 33612.
TI Cell transplantation for central nervous system
disorders. [Review] SO Critical Reviews in
Neurobiology. 8(3):125-62, 1994.
AB Initially, the specific aim of transplantation
studies was to investigate the regenerative
capabilities of the mammalian nervous system.
From this underlying impetus, a myriad of
knowledge, spanning from molecular biology to
neurobiology, has enhanced our understanding of
regeneration and the applicability of fetal tissue
transplantation in treating various
neurodegenerative diseases. Current evidence
suggests that transplantation of fetal neural tissue
ameliorates the neurobiological and behavioral
changes observed in animal models of central
nervous system (CNS) disorders. In light of
numerous basic science studies, clinical trials have
begun to evaluate the potential of neural
transplantation in treating human diseases.
Indeed, modest progress has been reported in the
treatment of Parkinson's disease. However,
whereas fetal tissue transplantation has reached
considerable success, it has also been observed to
produce either no beneficial effects, magnify
existing behavioral abnormalities, or even produce
a unique constellation of deficits. Thus, while the
prospects are promising, further investigations
aimed at improving and refining existing
transplantation paradigms are warranted before
neural transplantation techniques can be of
widespread value. This review article attempts to
provide an overview of the neuroanatomical,
neurochemical, and behavioral effects produced
by transplanted fetal tissue in several animal
models of CNS disorders. We have attempted to
present both positive and adverse effects and to
critically analyze the suitability of neural
transplantation as a therapy for the various
neurological disorders. In addition, alternative
approaches, including the use of encapsulated
neural tissue implants and genetically engineered
cell lines along with their clinical potential, are
discussed when appropriate. [References: 275]
 
AN 93283757
AU Widner H. Rehncrona S.
IN Department of Neurology, University Hospital,
Lund, Sweden. TI Transplantation and surgical
treatment of parkinsonian syndromes. [Review]
SO Current Opinion in Neurology &
Neurosurgery. 6(3):344-9, 1993 Jun.
AB Neurosurgical attempts to correct
parkinsonism use strategies aimed either at
alleviating the underlying dopamine deficiency or
at correcting abnormal compensatory effects in
neural circuits within the basal ganglia. During
the review period, clinical trials of four different
neurosurgical approaches were reported. These
approaches are intracerebral transplantation of
fetal dopamine neurons, intracerebral
transplantation of adrenal medullary tissue,
tremor-reducing surgical lesions in the
ventrolateral thalamus, and ventroposterior
pallidotomy aimed at reducing akinesia and
rigidity. Experimental studies in rats and monkeys
designed to explore mechanisms of graft actions
were also reported. [References: 33]
 
AN 93063066
AU Widner H. Tetrud J. Rehncrona S. Snow B.
Brundin P. Gustavii B. Bjorklund A. Lindvall O.
Langston JW.
IN Department of Neurology, University Hospital,
Lund, Sweden. TI Bilateral fetal mesencephalic
grafting in two patients with parkinsonism
induced by 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) [see comments].
SO New England Journal of Medicine.
327(22):1556-63, 1992 Nov 26. AB
BACKGROUND. Intracerebral transplantation of
fetal dopaminergic neurons is a promising new
approach for the treatment of Parkinson's disease.
Patients with parkinsonism induced by 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have
a relatively stable lesion limited to the nigrostriatal
system, rendering them ideal candidates for
transplantation. Improvement of motor function
after neural grafting has previously been observed
in nonhuman primates with MPTP-induced
parkinsonism. METHODS. We grafted human
fetal tissue from the ventral mesencephalon
(obtained six to eight weeks after conception)
bilaterally to the caudate and putamen in two
immunosuppressed patients with severe MPTP-
induced parkinsonism, using a stereotaxic
technique. The patients were assessed regularly
with clinical rating scales, timed tests of motor
performance, and [18F]fluorodopa positron-
emission tomography during the 18 months before
the operation and the 22 to 24 months after the
operation. RESULTS. Both patients had
substantial, sustained improvement in motor
function and became much more independent.
Postoperatively, the second patient's maintenance
dose of levodopa was decreased to 150 mg daily,
which was 30 percent of the original dose. Striatal
uptake of fluorodopa was unchanged 5 to 6
months postoperatively but was markedly and
bilaterally increased at 12 to 13 and 22 to 24
months in both patients, closely paralleling the
patients' clinical improvement. There were no
serious complications. CONCLUSIONS. Bilateral
implantation of fetal mesencephalic tissue can
induce substantial long-term functional
improvement in patients with parkinsonism and
severe dopamine depletion and is accompanied by
increased uptake of fluorodopa by the striatum.
The results in these patients resemble those
obtained in MPTP-treated primates and suggest
that this will be a useful model for the assessment
of transplantation therapies in Parkinson's
disease.
 
AN 93063065
AU Freed CR. Breeze RE. Rosenberg NL. Schneck
SA. Kriek E. Qi JX. Lone
Zhang YB. Snyder JA. Wells TH. et al.
IN University of Colorado Health Sciences Center,
Denver 80262. TI Survival of implanted fetal
dopamine cells and neurologic improvement 12 to
46 months after transplantation for Parkinson's
disease [see comments].
SO New England Journal of Medicine.
327(22):1549-55, 1992 Nov 26.
AB BACKGROUND AND METHODS. Patients
with Parkinson's disease tend to have a reduced
response to levodopa after 5 to 20 years of
therapy, with "on-off" fluctuations consisting of
dyskinesia alternating with immobility. In an
effort to modify the motor disability of advanced
Parkinson's disease, we implanted embryonic
mesencephalic tissue containing dopamine cells
into the caudate and putamen of seven patients.
Two patients received unilateral grafts in the
caudate and the putamen on the side opposite the
side with worse symptoms. Five patients received
bilateral grafts implanted in the putamen only. In
six of the seven patients, the fetal tissue was
obtained from a single embryo with a gestational
age of seven to eight weeks. The tissue was
injected by means of 10 to 14 needle passes. There
were no surgical complications. Four of the seven
patients underwent immunosuppression with
cyclosporine and prednisone. RESULTS. All
patients reported improvement according to the
Activities of Daily Living Scale when in the on
state 3 to 12 months after surgery (P < 0.01).
Neurologic examination according to the Unified
Disease Rating Scale showed that five of the seven
patients improved when in the on state six months
after surgery. The mean group Hoehn-Yahr score
improved from 3.71 to 2.50 (P < 0.01). Computer
and videotape testing in the home supported these
findings. Fluctuations in clinical state were
moderated, and periods of dyskinesia and off
episodes were shorter and less severe than before
implantation. Drug doses were reduced by an
average of 39 percent (P < 0.01; maximum, 58
percent). The results of cliniical evaluation and
fluorodop positron-emission tomography in one
patient were compatible with transplant survival
for as long as 46 months. Both immunosuppressed
and nonimmunosuppressed patients improved.
CONCLUSIONS. Fetal-tissue implants appear to
offer long-term clinical benefit to some patients
with advanced Parkinson's disease.
 
AN 93063064
AU Spencer DD. Robbins RJ. Naftolin F. Marek
KL. Vollmer T. Leranth C. Roth RH. Price LH.
Gjedde A. Bunney BS. et al.
IN Neural Transplant Program, Yale University
School of Medicine, New Haven, Conn. 06510.
TI Unilateral transplantation of human fetal
mesencephalic tissue into the caudate nucleus of
patients with Parkinson's disease [see comments].
SO New England Journal of Medicine.
327(22):1541-8, 1992 Nov 26. AB
BACKGROUND. Parkinson's disease is
characterized by the loss of midbrain
dopamine neurons that innervate the caudate and
the putamen. Studies in animals suggest that fetal
dopaminergic neurons can survive transplantation
and restore neurologic function. This report
compares the clinical results in four case patients
with severe Parkinson's disease who underwent
stereotaxic implantation of human fetal ventral
mesencephalic tissue in one caudate nucleus with
the results in a control group of similar subjects
assigned at random to a one-year delay in surgery.
METHODS. Each case patient received
cryopreserved tissue from one fetal cadaver
(gestational age, 7 to 11 weeks). Before
implantation, adjacent midbrain tissue underwent
microbiologic, biochemical, and viability testing.
Cyclosporine was administered for six months
postoperatively. RESULTS. The procedure was
well tolerated. Three case patients showed
bilateral improvement on motor tasks, as assessed
on videotape, and were more functional in the
activities of daily living, as assessed by themselves
and neurologists, during both optimal drug
therapy and "drug holiday" periods. One case
patient, who died after four months from
continued disease progression, had striatonigral
degeneration at autopsy. In the patients who
received transplants, optimal control was achieved
with a lower dose of antiparkinsonian
medications, whereas the controls required more
medication. Positron-emission tomography with
[18F]fluorodopa before and after surgery in one
patient revealed a bilateral restoration of caudate
dopamine synthesis to the range of normal
controls, but continued bilateral deficits in the
putamen. CONCLUSIONS. Although the case
patients continued to be disabled by their disease,
unilateral intracaudate grafts of fetal tissue
containing dopamine diminished the symptoms
and signs of parkinsonism during 18 months of
evaluation.
 
AN 93044295
AU Bjorklund A.
IN Department of Medical Research, University of
Lund, Sweden. TI Dopaminergic transplants in
experimental parkinsonism: cellular mechanisms
of graft-induced functional recovery. [Review]
SO Current Opinion in Neurobiology. 2(5):683-9,
1992 Oct.
AB The ability of intrastriatal grafts of fetal
mesencephalic dopamine neurons to ameliorate
the symptoms of experimental and clinical
parkinsonism has raised the question of the
mechanisms underlying the transplant-induced
functional effects. Recent studies have taken
advantage of quantitative cytochemical and in situ
hybridization techniques to study functional graft-
host interactions at the cellular level in the rat
Parkinson model. The results provide evidence
that behaviorally functional grafts restore
dopaminergic neurotransmission and normalize
dopamine receptor function in the denervated
striatum, and that these effects are likely to
depend on both synaptic and extrasynaptic
mechanisms. [References: 51]
 
AN 92246461
AU Sawle GV. Bloomfield PM. Bjorklund A.
Brooks DJ. Brundin P. Leenders KL. Lindvall O.
Marsden CD. Rehncrona S. Widner H. et al.
IN Medical Research Council Cyclotron Unit,
Hammersmith Hospital, London, England.
TI Transplantation of fetal dopamine neurons in
Parkinson's disease: PET [18F]6-L-fluorodopa
studies in two patients with putaminal implants.
SO Annals of Neurology. 31(2):166-73, 1992 Feb.
AB Two patients with Parkinson's disease who
underwent implantation of fetal mesencephalic
tissue into the putamen were serially studied using
positron emission tomography and [18F]6-L-
fluorodopa ([18F]dopa). The uptake of [18F]dopa
is related to the functional integrity of the
presynaptic dopaminergic system. Preoperative
studies revealed a marked decrease in putamen
[18F]dopa uptake, with lesser involvement of the
caudate. Two and 4 months, respectively, after
operation, both patients demonstrated functional
improvement, as described elsewhere. One patient
was scanned 5, 8, and 13 months after the
operation and the other was scanned 7 and 12
months after the operation. In both patients,
[18F]dopa uptake increased within the operated
putamen despite a progressive decrease in tracer
uptake in the unoperated striatal structures. We
believe that this increased uptake of [18F]dopa at
the implantation site represents functional
integrity within a surviving neural graft. While
there has been little further clinical improvement
beyond the fifth postoperative month, the uptake
of [18F]dopa at the operation site in both patients
has progressively increased. The kinetic data
provide evidence of disease progression in the
unoperated striatum, which, balanced against
increasing graft function, may explain why clinical
improvement reached a plateau within months
after surgery.
 
AU Lindvall O. Widner H. Rehncrona S. Brundin
P. Odin P. Gustavii B. Frackowiak R. Leenders
KL. Sawle G. Rothwell JC. et al.
IN Department of Neurology, University Hospital,
Lund, Sweden. TI Transplantation of fetal
dopamine neurons in Parkinson's disease: one-
yearclinical and neurophysiological observations
in two patients with putaminal implants.
SO Annals of Neurology. 31(2):155-65, 1992 Feb.
AB Ventral mesencephalic tissue from aborted
human fetuses (age, 6-7 weeks' postconception)
was implanted unilaterally into the putamen using
stereotaxic surgery in 2 immunosuppressed
patients (Patients 3 and 4 in our series) with
advanced idiopathic Parkinson's disease. Tissue
from 4 fetuses was grafted to each patient.
Compared with our previous 2 patients, the
following changes in the grafting procedure were
introduced: the implantation instrument was
thinner, more tissue was placed in the operated
structure, and the time between abortion and
grafting was shorter. There were no postoperative
complications. Both patients showed a gradual
and significant amelioration of parkinsonian
symptoms (most marked in Patient 3) starting at 6
and 12 weeks after grafting, respectively, reaching
maximum stability at approximately 4 to 5
months; patients remained relatively stable
thereafter during the 1-year follow-up period.
Clinical improvement was observed as a reduction
of the time spent in the "off" phase and the
number of daily "off" periods; a lessening of
bradykinesia and rigidity during the "off" phase,
mainly but not solely on the side contralateral to
the graft; and a prolongation and change in the
pattern of the effect of a single dose of L-dopa.
Neurophysiological measurements revealed a more
rapid performance of simple and complex arm and
hand movements bilaterally, but primarily
contralateral to the graft. The results indicate that
patients with Parkinson's disease can show
significant and sustained improvement of motor
function after intrastriatal implantation of fetal
dopamine-rich mesencephalic tissue. The
accompanying paper by Sawle and colleagues
describes the results of repeated positron emission
tomography scans in these patients.
 
AN 89272713
AU Lindvall O. Rehncrona S. Brundin P. Gustavii
B. Astedt B. Widner H. Lindholm T. Bjorklund A.
Leenders KL. Rothwell JC. et al.
IN Department of Neurology, University of Lund,
Sweden.
TI Human fetal dopamine neurons grafted into
the striatum in two patients with severe
Parkinson's disease. A detailed account of
methodology and a 6-month follow-up.
SO Archives of Neurology. 46(6):615-31, 1989
Jun.
AB By using stereotaxic surgical techniques,
ventral mesencephalic tissues from aborted human
fetuses of 8 to 10 weeks' gestational age were
implanted unilaterally into the striata in two
patients with advanced Parkinson's disease. The
patients were treated with a cyclosporine,
azathioprine, and steroid regimen to minimize the
risk for graft rejection. They were examined for 6
months preoperatively and 6 months
postoperatively and continued to receive the same
doses of antiparkinsonian medication. There were
no significant postoperative complications. No
major therapeutic effect from the operation was
observed. However, in the clinical tests, both
patients showed small but significant increases of
movement speed for repeated pronation-
supination, fist clenching, and foot lifting. The
rate of walking also increased in the one patient
tested. For both patients, there was an initial
worsening postoperatively, followed by
improvement vs preoperative performance at 1 to
3 months. Both patients also showed significant
improvement in the magnitude of response to a
single dose of levodopa (L-dopa), but there was no
increase in the duration of drug action. The motor
readiness potential increased in both patients
postoperatively, primarily over the operated
hemisphere. Neurophysiological measurements
also showed a more rapid performance of simple
and complex arm and hand movements on the side
contralateral to transplantation in one patient at 5
months postoperatively. Positron emission
tomography demonstrated no increased uptake of
6-L-(18F)-fluorodopa in the transplanted striatum
at 5 and 6 months. Taken together, these results
suggest that the fetal nigral implants may have
provided a modest improvement in motor
function, consistent with the presence of small
surviving grafts. Although our results support
further scientific experimentation with
transplantation in Parkinson's disease, widespread
clinical trials with this procedure are probably not
warranted at this time.
 
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