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Wed May 4 21:00:00 2005 Pacific Time

       Clinical Study Results in Parkinson's Patients May Lead to
Development of Future Cell Transplantation Methods
        BELMONT, Mass., May 5 (AScribe Newswire) -- A report published in
the May 5 online version of the prominent journal Brain documents the first
post-mortem analysis of two patients with Parkinson's disease who received
human fetal midbrain transplants -- prepared as a cell suspension -- into
the striatum, and in one case, also into a novel surgical location: the
substantia nigra of the patient's brain.

        These patients showed marked and progressive clinical improvement
over a three-year period after transplantation that was accompanied by and
correlated with positive F-fluorodopa PET scans. Of clinical significance,
the patients did not develop any further motor complications after
transplantation. This is an important observation since recent studies --
using other cell preparation and implantation techniques -- have
occasionally resulted in disappointing and debilitating side effects.

        The study is a collaborative effort between researchers from
Harvard-affiliated McLean Hospital in Belmont, Mass., and Dalhousie
University in Halifax, Canada. The team, led by Ole Isacson, MD, director
of the Neuroregeneration Laboratory at McLean, collaborated with Ivar
Mendez, MD, the clinical principal investigator who transplanted the
Parkinson patients in a small exploratory clinical trial performed at Queen
Elizabeth II Health Science Center in Halifax.

        In this new clinical and post-mortem study, the McLean team, which
has developed the basic science and methods to analyze the cellular
composition of neural transplants and function of newly implanted dopamine
neurons, first identified markers of the most vulnerable dopamine cell
populations of the midbrain in cases of unaffected control human substantia
nigra. They found that a G-protein-coupled inward rectifying current
potassium channel type 2 (Girk2) co-localized with dopamine markers in such
vulnerable neurons, and then also demonstrated that such specific dopamine
neurons could survive when transplanted into the brains of Parkinson patients.

        The grafts, which were implanted by a technique where tiny pieces
of human fetal midbrain is first separated into single cells and then
infused into the patient's brain in a carrier liquid, managed to replace
the Parkinson patients' specific dopamine cell type that provides the
relevant axonal network to the most affected striatal regions in the disease.

        Of relevance to the ongoing scientific debate over the specific
need for transplant immune system suppression when using nerve cells, the
patients received anti-rejection drugs for only six months immediately
after surgery, yet the transplants integrated seamlessly and without
inflammatory or other signs of rejection at the post-mortem analysis three
to four years after surgery.

        The study included patients with severe disease, which shows that
using these methods, dopamine neuronal replacement cell therapy can be
beneficial for patients with advanced disease and perhaps, that changing
technical approaches could have a favorable impact on efficacy and adverse
events following neural transplantation.

        Olle Lindvall, MD, of Lund University in Sweden, a renowned
neurologist and researcher in gene and cell therapy for Parkinson's
disease, stated: "Some of the reasons for the discrepancies in outcome
between clinical studies are probably that grafting and tissue preparation
procedures are poorly standardized and that different patient selection
criteria are used. More knowledge about factors that determine the
functional outcome after transplantation is highly warranted for the
further advancement of the field and also for the success of future stem
cell-based approaches in Parkinson's disease."

        "This new paper in Brain represents an important step forward in
the field of cell therapy for Parkinson's patients," Lindvall continued.

        "The study includes two patients who showed clinical benefit and no
motor complications after transplantation. Most importantly, it provides
evidence that the composition of the graft with respect to its content of a
specific type of dopamine neuron, and whether the graft tissue is implanted
as a cell suspension or in pieces, is of crucial importance for the
efficacy and occurrence of adverse events in cell-replacement therapy," he
concluded.

        "These findings may provide the framework for designing future cell
and stem-cell therapies that can match or improve upon the most functional
fetal dopamine neuron transplants in Parkinson's disease," said Eugene
Redmond, MD, of Yale University, a leader in Parkinson's research, cell
replacement and drug discovery.

        While investigating control cases of human substantia nigra, the
scientists from McLean Hospital also demonstrated that dopamine neurons in
the human mid-brain with high expression of markers for Girk2 and absence
of calbindin, correspond to the dopamine neuron type that is selectively
lost in Parkinson's disease, and a cell known to project to the motor
striatum and participate in the regulate movement initiation.

        Many have questioned whether such vulnerable dopamine neurons can
survive implantation since there may be negative effects from the on-going
disease process in a patient's brain. However, the new study in Brain
demonstrates that such vulnerable neurons can indeed survive when implanted
into the brains of Parkinson patients.

        "This is a critical finding because it shows that the most
functionally adapted dopamine midbrain neuron type can survive, grow and
reinnervate the host putamen, even in Parkinson's disease patients, with
significant benefit to the patient and without side effects," said McLean
Hospital's Isacson, senior and corresponding author of the study, and
leader of the cell therapy research team at McLean Hospital.

        This is also the first analysis of a cellular graft placed in the
substantia nigra in a patient. "The functional benefit observed in these
patients, together with the absence of side effects, in particular,
dyskinesias, is encouraging," said Mendez, the clinical lead investigator,
professor and chairman of neurosurgery at Dalhousie University.

        The use of cell suspensions may cause fewer side effects than other
methods, since 90 percent of patients to date receiving cell-suspension
grafts have not experienced the severe off-phase dyskinesias that were so
problematic in recent clinical trials using solid-tissue pieces as a
surgical approach. Instead, using cell-suspension transplants (similar to
the new study reported in Brain), such patients have experienced beneficial
effects for at least 12 to 14 years after cell implantation, according to
an on-going Swedish study.

        Said Isacson: "This is the first in-depth study of the cellular
composition, survival and integration of successful dopamine-containing
suspension grafts in Parkinson's disease patients. These findings may
provide clues for designing future trials: for example, using stem
cell-derived dopamine neurons. This is still a relatively new research
field and the Canadian studies demonstrate that dopamine neuron replacement
therapies can be effective in patients even at late stages of the disease
and that subtle changes in cell preparation and transplant methodology may
result in different clinical outcomes."

        These collaborative teams in Belmont, Mass. and Halifax now aim to
use this new understanding of specific cellular components of functional
transplants for effective cellular, stem cell and synaptic restorative
neurological therapies.

        McLean Hospital, consistently ranked the nation's top psychiatric
hospital by U.S. News & World Report, is an affiliate of Harvard Medical
School and Massachusetts General Hospital, and a member of Partners
HealthCare.

        - - - -

        CONTACTS: Cindy Lepore, 617-855-2110

        For comments by external non-affiliated experts:

        Professor Eugene Redmond, MD, PhD, Yale University School of
Medicine, 333 Cedar St., New Haven, CT 06520, 203-773-9300,
[log in to unmask]

        Professor Warren Olanow, MD, Mount Sinai Medical Center, Dept. of
Neurology, 1 Gustave L. Levy Place, New York, NY 10029, 212-241-8435,
[log in to unmask]

        Professor Olle Lindvall, MD, PhD, Lund University, Wallenberg
Neuroscience Center, Lund, SE-22185, Sweden, +46-46-222-0543,
[log in to unmask]

       Media Contact: Cindy Lepore, 617-855-2110

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