The Neurosciences Institute, which is associated with Good Samaritan
Hospital in Los Angeles, sponsored a symposium on Nov. 2-3, 1996
in Rancho Mirage, CA. Dr. Kopyov made his presentation there.

I thank Carole Hilton for making this information available to the
Parkinsn archives.



Neurotransplantation for Parkinson's disease and Huntington's
disease

Oleg V. Kopyov, PhD, MD

INTRODUCTION

        Neurotransplantation represents a potential for
neurodegenerative diseases with a focused region of cell death
Its potential is based on the strategy of neuronal replacement
with developing fetal neurons, which can establish connections
with the remaimng host neurons to restore functionality to the
region. This rationale is supported by animal studies which have
demonstrated that in models of Huntington's and Parkinson's
disease, transplanted fetal tissue integrates with host brain
and ameliorates some behavioral deficits. while this approach
may provide a new means of treatment for intractable disease,
some concerns remain as to the safety of placing partially
characterized fetal tissue into the brains of disease patients.
The foremost of these concerns along these lines are the risk of
tissue overgrowth which might crowd the existing brain tissue,
the risk of intraparenchymal infection, and the possibility that
the risks of neurosurgery will not be balanced by the benefits
of neurotransplantation.
        Transplantation of fetal tissue for two Parkinson's disease
patients has recently demonstrated that neurotransplantation was
a safe and feasible procedure for PD patients. The many patients
which have now undertaken transplantation for PD have generally
demonstrated good outcomes, with enough improvement in movement
dysfunctions to outweigh the risks of neurosurgery. Tissue
grafts appear to survive well within the brain, and motor
deficits are improved in most patients receiving transplants.
None of the patients receiving fetal grafts have demonstrated
any evidence of graft overgrowth, nor have they become infected
as a result of transplantation despite prolonged periods of
immunosuppression to prevent graft rejection.
        The positive results of neurotransplantation for PD have led to
consideration of fetal neurotransplantation to ameliorate the
symptoms of HD. Transplants of fetal striatum (a region termed
the lateral ganglionic eminence; (LGE) placed in the lesioned
striatum of adult rats have been shown to survive, integrate with
the host, and express markers typical of striatal tissue. Grafts
of human fetal striatal precursors placed into rat striatum have
demonstrated striatal markers and outgrowth which was
constrained to anatomically appropriate regions. These rats
demonstrated functional recovery from the strintal lesion as
well. Together with the clinical findings that
neurotransplantation can be an effective treatment for PD, these
animal studies suggest that transplantation may be safely
undertaken for HD patients.
        Given the evidence of potential benefits of neurotransplantation
for HD patients, and the lack of any other effective treatment, the
Neurosciences Institute has undertaken transplantation
for a small number of carefully chosen HD patients. The first
three HD transplantation patients have been evaluated up to 44
weeks following surgery. MR images of the transplants
demonstrate contained, healthy grafts with no overgrowth and
suggest that neurotransplantation is safe for HD patients.


METHODS

        This protocol was approved by the Institutional Review Board of
Good Samaritan Hospital, Los Angeles (IRB# 95-04-06).
Diagnostic criteria and implementation of this protocol were
based on recommendations from the Core Assessment Program for
Intracerebral Transplantation for Huntington's Disease (CAPIT-
HD). Inclusion and exclusion criteria are presented in Table 1.
Bach patient understood and signed an informed consent form, and
then entered a baseline evaluation after the diagnosis of HD was
confirmed through DNA analysis and MR imaging revealing the
presence of atrophied caudate and putamen of a size sufficient
to permit the stereotactic implantation of five needle tracks in
each hemisphere. The baseline evaluation phase lasted for 3 to 6
months. During this time, patients' neurological status was
evaluated by a neurologist utilizing a videotaped motor and
functional assessment utilizing the Unified Huntington's
Disease Rating Scale (UHDRS). MRI and deoxyglucose PET scans
were performed 6 and 12 months after surgery. The MRI images
obtained immediately prior to surgery were used to calculate
stereotactic coordinates for one needle track in the caudate
nucleus and four in the putamen using GammaPlan software
(Version 2.01, Flekta, Sweden).


RESULTS

        The clinical neurological outcomes of the patients demonstrated
substantial improvement in balance and mobility within two weeks
following surgery, as shown by increased ability to walk and
stand without assistance. The changes in behavioral symptoms
such as aggressive or disruptive behavior and depressive
episodes were variable, with frequency and intensity decreased
in two patients and increased in one. Chorea and dystonia were
decreased in all patients. All patients displayed increased
ability to function in daily tasks ranging from taking own
medications to dressing oneself and preparing meals. When
evaluated six months following surgery, these improvements
remained steady or increased. Patients will continue to be
evaluated for future changes in symptoms.
        All three patients recovered well from surgery, with no adverse
effects noted. Patient profiles are presented in Table 2. The
day following surgery, MR images demonstrated four
transplantation tracks placed into the putamen and one needle
track in the caudate nucleus of each hemisphere, as targeted. In
all patients the grafting sites demonstrated minimal edema.
        Five to six months following surgery, MR images demonstrated
no evidence of edema. An intermediate signal intensity was
visible in the striatum at the site of the fetal implants This
signal was increased in intensity over that observed in the
previous postoperative images, which is consistent with fetal
tissue growth. Although larger, the bodies of the grafts were
constrained within the confines of the striatum such that the
contours of the fetal grafts reflected those of the striatum.
Narrow streaks of increased signal intensity were apparent
extending from the fetal grafts toward the internal capsule,
however, suggesting extension of processes from the grafts to
the host tissue.
        In the first patient, new areas of low density were observed
within the right caudate nucleus and basal ganglia. These areas
exhibited a signal similar to that of cerebrospinal fluid,
suggesting that they may represent regions of porencephaly or
remote infarct. No discrete changes were observed in the left
caudate nucleus of this patient.


DISCUSSION

        The success of neurotransplantation in the treatment of
Parkinson's disease, has raised its consideration as an option
for Huntington's disease patients. The current study reports on
the treatment of three HD patients with neurotransplantation,
and describes the morphological outcomes as visualized with MRI.
Together with clinical improvements in symptoms and mobility,
these results provide evidence that neurotranspiantation is a
safe procedure for HD patients.
        A primary concern with grafting tissue to the brain is
unconcontrolled graft overgrowth. None of the three patients
receiving intrastriatal neurotransplantation of human fetal LGE
exhibited graft overgrowth six months following grafting. This
finding agrees with the majority of transplantation studies
performed in rats and primates, which have reported constrained
growth of fetal allografts. Transplantation of nigral tissue for
PD has not been shown to result in graft overgrowth in any
patient. The constrained distribution of the fetal LGE grafts in
the present HD patients provides support for the safety of
striatal neurotransplantation.
        The grafted tissue did demonstrate a constrained degree of
growth within the striatum, which is consistent with the natural
growth of fetal tissue during the course of six months. Fine
tissue processes were also observed to extend medially from the
graft bodies. These processes resemble those observed in animal
studies of neurotransplantation. In the rat, grafts of fetal rat
LGE and MGE placed in denervated striatum extend processes to
appropriate target regions, establishing functional connections.
The presence of such extensions emanating from fetal grafts in
HD patients suggest that these grafts may be establishing
similar connections with previous targets of the degenerated
striatum.
        In one patient, a postsurgery complication became
visible on MR images, appearing to be either porencephaly or
remote infarct. The patient has not displayed any adverse
effects which may be attributable to such a complication,
although he has exhibited a lesser degree of improvement than
the other two patients.
        These clinical and morphological outcomes of the first
three HD patients to receive fetal striatal
neurotranspiantation has demonstrated that there is no
uncontrolled overgrowth of the transplanted tissue, and that the
potential benefits from the procedure do appear to merit the
risks of neurosurgery. These results provide evidence for the
safely of neurotransplantation HD patients. The potential of
this approach as a treatment for HD will be further pursued,
following the same standardized guidelines to select and
evaluate future patients.

[log in to unmask]      That man may last, but never lives,
                        Who much receives, but nothing gives;
HomeBoy #Parkinsons         Whom none can love, whom none can thank,--
                               Creation's blot, creation's blank.
John Cottingham           Thomas Gibbons (1720-1785): When Jesus dwelt.