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Clinical study results in Parkinson's patients may lead to development of future cell transplantation methods

FOR IMMEDIATE RELEASE:
May 05, 2005

CONTACT:
Cynthia Lepore
Public Affairs
617/855-2110

Belmont, MA - A report (PubMed) 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.

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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, eugene.redmond@yale.edu

Professor Warren Olanow, MD, Mount Sinai Medical Center, Dept. of Neurology, 1 Gustave L. Levy Place, New York, NY 10029, (212) 241-8435, warren.olanow@mssm.edu

Professor Olle Lindvall, MD, PhD, Lund University, Wallenberg Neuroscience Center, Lund, SE-22185, Sweden, +46-46-222-0543, olle.lindvall@neurol.lu.se

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