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Investigators Create Functional Dopamine Neurons: Clinical Trials in PD Could Be A Few Years Away

Talan, Jamie

doi: 10.1097/01.NT.0000410064.13857.65
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Investigators report that they were able to make pure and functional dopamine neurons from human embryonic stem cells and are observing their effects in a non-primate model of Parkinson disease.

Scientists think they have finally found the right recipe to make pure and functional dopamine neurons from human embryonic stem cells (hESCs), a feat that could mean an abundant source of cells for transplantation in Parkinson disease (PD) patients in the next five years.

Frustrated by animal studies that failed to show an improvement in PD symptoms with dopamine neurons made from hESCs, Lorenz Studer, MD, director of the Laboratory of Stem Cell & Tumor Biology, Neurosurgery and Developmental Biology, and his colleagues at Memorial Sloan-Kettering Cancer Center in New York City focused on trying to discovered a key signal to create a population of dopamine neurons that worked to restore dopamine in the brain.

They described their findings in a paper in the Nov. 6 online edition of Nature.

The field was initially excited by the mouse embryonic stem (ES) cell data that showed the embryonic cells could be coaxed into becoming dopamine neurons and, when transplanted, the animals with PD symptoms seemed to improve. Similar studies using hESCs never went beyond success in a petri dish. When they were transplanted into the brains of animals, the dopamine neurons either did not survive or those that did lost their identity. Worse, a subset of other cells in the graft tended to grow, causing concerns about tumor formation.



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Looking at the cells in the laboratory, Dr. Studer said that they had about 80 percent of the right properties necessary to call them a midbrain dopamine cell. But something was preventing them from maintaining their fate. They tried many different signals and eventually found that activating Wnt signaling at exactly the right time and point created a population of dopamine neurons that work “extremely well in animal models of Parkinson disease,” said Dr. Studer. [Wnt signaling involves a network of proteins known for their roles in embryogenesis and cancer, but is also involved in normal physiological processes in adult animals.]

Using midbrain floor plate precursors derived from human pluripotent stem cells 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical Wnt signaling, they created a population of midbrain dopamine neurons that remained viable in vitro for several months. A series of biochemical and electrophysiological data confirmed their dopamine identity. Populations were grafted into rats and mice and monkeys. These studies confirmed substantial survival of the dopamine neurons and restoration of various symptoms associated with the Parkinson model.

The final proof that the technique was working would come from scaling up the population of dopamine cells for transplantation in monkeys. They grew 20 times more cells than needed in the mouse and rat studies and transplanted them along six different tracks in the brain. The cells remained abundant and functional. The transplanted cells did not lead to neural overgrowth, which had been a problem with earlier sources of dopamine neurons.

In the past, the field used two signals — sonic hedgehog, which plays a key role in regulating vertebrate organogenesis, such as in the growth of digits on limbs and organization of the brain — and FGF8 (fibroblast growth factor 8). But it was the addition of the Wnt signal that was critical for the cells to find their true identity. With the three signals, the floor-plate precursors get the message to become midbrain dopamine neurons.

“I think the cells will last for years,” said Dr. Studer.

The investigators are now working on ways to produce large populations of these cells for possible use in clinical studies. They will build a master bank of these human ES- derived dopamine neurons. Memorial Sloan-Kettering has a facility where they can manufacture cells for use in humans, Dr. Studer said, but it could take a few years to develop and test such a master bank.

Meanwhile, the research team will keep the parkinsonian monkeys that received the transplanted dopamine neurons alive for one year to ensure that the animals do not develop any side effects from the cells.

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The initial excitement about the new cell formations recalls earlier response to efforts to transplant fetal cells to PD in 1988. The fetal material came from aborted tissue so it was impossible to obtain a pure batch of dopamine cells. Twelve years later, the results from the first double-blind study to test the benefits of fetal cells in PD patients brought a halt to the procedure. As reported in 2001 in the New England Journal of -Medicine, some older patients in the study, those over 60, developed dyskinesia from the transplanted tissue.

“No one got better than the best effects of L-dopa,” said Curt R. Freed, PhD, professor of medicine and pharmacology at the University of Colorado School of Medicine. Dr. Freed, who pioneered the use of the fetal cell transplants, observed 61 transplant procedures. “The experiments with fetal dopamine cell transplants taught us everything these cells can do.”

While the technique did not alter the course of the disease, some of the transplanted cells did what they were designed to do: make dopamine. It was never as effective as L-dopa but there were some patients who could lower their dose after the transplant.

Dr. Freed said that the controversy over the use of tissue from aborted fetuses and the difficulty of recovering dopamine neurons from fetal brain cells made the decision easy to turn their research attention to hESCs.

“There have been a lot of arguments in the field over the recipe to make dopamine neurons,” said Dr. Freed. The problem, he said, is that scientists need enough surviving dopamine cells to have a behavioral effect.

“The strong behavioral data in Lorenz Studer's paper is an endorsement that his recipe works,” said Dr. Freed. His group recently described the genetic profile in mouse ES-derived dopamine neurons. They are now able to use this genetic fingerprint to test the true identify of mouse ES cell-derived dopamine neurons.

It will be necessary to be able to have this genetic proof of identify in human lines that are created, Dr. Freed said.

Of the latest Nature study, he added: “I congratulate the scientists. They have brought a lot of thought to this strategy.”

“It is a good advance,” said Steven A. Goldman, MD, PhD, professor and chairman of the department of neurology at the University of Rochester. “They created a protocol to yield a more specific population of mid-brain dopamine neurons that do not appear to be tumorigenic. They have also extended the technique to iPS cells and this opens up the possibility for patient-specific therapies.”

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• Kriks S, Shim JW, Studer L, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 2011; E-pub 2011 Nov 6.
    • Freed CR, Zhou W, Breeze RE. Dopamine cell transplantation for Parkinson's disease: the importance of controlled clinical trials. Neurotherapeutics 2011;8(4):549-561.
      • Freed CR, Greene PE, Fahn S, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2011;344:710-719.
        ©2011 American Academy of Neurology