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Fetal-cell Transplants Reverse Parkinson’s in Two Patients
The video shows an elderly woman walking down a poorly lit corridor, halting and shaking with each shuffling step. She has suffered from Parkinson’s disease for 15 years. Then it cuts to a new scene: the same hallway, the same patient, but now she strides quickly down the hallway, still uncoordinated on one side, but vastly improved. The patient is no longer taking medications for Parkinson’s; instead, she is one of about 200 patients worldwide who have received a transplant of fetal brain tissue.
Photo by Graham Ramsay
“This is just the very beginning of cell therapy in medicine,” said Ole Isacson (right), pictured with lab members Angel Viñuela (left) and Daniela Ferrari.
“This improvement has been shown reliably in select patients,” said Ole Isacson, HMS professor of neurology at McLean Hospital. He has been collaborating with a clinical team in Halifax, Nova Scotia, led by Ivar Mendez, professor of anatomy and neurobiology at Dalhousie University, to improve the efficacy and safety of this experimental treatment. The patient in the video is one of a series to receive cells in a new form that Isacson believes may overcome problems with previous transplant methods. In the May 5 online edition of Brain, he and Mendez publish results of the first postmortems, which involve two patients who received the same type of transplant as the woman in the video and offer encouraging evidence that cell-based therapies can work.
Two Steps Back
The first transplants of brain tissue from aborted embryos into people with
Parkinson’s disease began in the late 1980s. The cells seemed to survive,
integrate into the brain, and produce dopamine; physicians saw their patients
make marked improvements. But when the method underwent placebo-controlled
phase II clinical trials, the results dealt a blow to the endeavor. The therapy
did not show a significant improvement across all patients, while some of
the patients experienced severe uncontrolled shaking as a side effect of
the procedure,
prompting many people to question whether the therapy was too dangerous for
humans.
In Isacson’s view, the trials came before the method had been sufficiently developed. These trials used small pieces of tissue taken from the midbrains of aborted embryos. This latest study tested an alternative method, cell suspension, in which the cells are chemically dissociated before being implanted. Although the patients in Mendez’s group have been showing improvements, as have another group of patients who received cell suspension transplants in Sweden, this is the first postmortem analysis to verify that the grafted cells have done what they were intended to do.
| “These patients were not cured, but they had a reversal of disease back to a level slightly better than when they were on drugs five to ten years ago.” |
The two patients were part of a small exploratory study at Queen Elizabeth
II Health Science Center in Halifax. In the study, the cells were bathed in
the trophic factor GDNF before being implanted into the striatum,
the target of dopamine-producing
cells. One patient also had cells im-planted into the substantia nigra, the
origin of the dopamine neurons involved in Parkinson’s.
The study provides an in-depth picture of both the clinical improvements in the patients and the physiological outcomes of the experiment. The two patients both experienced progressive improvement in symptoms over a three- to four-year period after their transplantation—both died of unrelated causes. The patients also showed positive PET scans for dopamine activity in the regions where grafts had been placed. In their postmortem analysis, Isacson’s team found dopamine-producing neurons along the graft sites, representing about a 10 to 30 percent survival rate in the putamen and slightly lower survival rate in the substantia nigra.
“These patients were not cured,” Isacson said, “but they had a reversal of disease back to a level slightly better than when they were on drugs five to ten years ago.” The analysis also found that there was little sign of excess inflammation caused by the grafts, and the patients had no negative side effects.
This is the first reported evidence that cells can survive and form connections in the substantia nigra, which Isacson believes may be an important target for future transplant therapies. The postmortem findings also closely correlate to clinical improvements. In one patient, the procedure was not completed on the left side because of abnormal bleeding. No cells grew in that part of the brain, and the patient had no functional recovery on the corresponding side of the body.
Selective Transplantation
Isacson’s team believes it can continue to improve cell-based therapies
for Parkinson’s disease by better characterizing and controlling specific
populations of cells. In Parkinson’s disease, the cells in the
A9 region of the substantia nigra are radically reduced in relation
to those
in the neighboring
A10 region, and Isacson believes that future therapies should focus
on boosting the A9 subpopulation of cells. His lab has found that in
rat models,
transplants
are more successful with a higher ratio of A9 neurons. Isacson thinks
that A10 neurons operate much more like unchecked dopamine pumps, which
may
explain why motor problems would result from the wrong mix of cells.
By analyzing tissue from the Harvard Center for Neurodegeneration and Repair’s Brain Bank, Isacson’s lab has found that a protein called Girk2 is more highly expressed in A9 neurons than in those from A10. Using a marker for this subpopulation of neurons, they confirmed for the first time that A9 cells had survived and functioned in the two patients. They are now working on ways to sort out the A9 cells from neuronal populations to better select cells for transplant. For Isacson, verifying the efficacy of the cell suspension method is an important advance because it allows researchers to more carefully control the types of cells given to the patient. Most proponents of cell-based therapies are looking to cultivate a more reliable source of transplantable cells using embryonic stem cells. With the confirmation that implanted cells of the right type can aid patients, Isacson’s lab is looking for ways to coax stem cells to differentiate into a stable population of A9 neurons.
Michele Tagliati, an associate professor of neurology at Mount Sinai School of Medicine in New York, said that while many neurologists have considered cell transplantation to be “on hold,” this study raises the possibility that a better method could renew interest in the technique. “Aside from the fact that the patients did well,” he said, “what is fairly convincing is the fact that these cell suspension implants seem to have a better integration with the host.”