M

ice that walk straight and fluidly dont usually make scientists exult, but these did: The lab rodents all had a mouse version of Parkinsons disease and only weeks before had barely been able to lurch and shuffle around their cages.

Using a trick from stem-cell science, researchers managed to restore the kind of brain cells whose death causes Parkinsons. And the mice walked almost normally.The same technique turned human brain cells, growing in a lab dish, into the dopamine-producing neurons that are AWOL in Parkinsons, scientists at Swedens Karolinska Institute reportedon Monday in Nature Biotechnology.

Success in lab mice and human cells is many difficult steps away from success in patients. The study nevertheless injected new life into a promising approach to Parkinsons that has suffered setback after setback replacing the dopamine neurons that are lost in the disease, crippling movement and eventually impairing mental function.

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This is not going to happen in five years or possibly even 10, but Im excited about the potential of this kind of cell replacement therapy, said James Beck, chief scientific officer of the Parkinsons Foundation, which was not involved in the study. It could really give life back to someone with Parkinsons disease.

There is no cure for Parkinsons, a neurodegenerative disease that affects an estimated 10 million people worldwide, most prominently actor Michael J. Fox. Drugs that enable the brain to make dopamine help only somewhat, often causing movement abnormalities called dyskinesia as well as bizarre side effects such as a compulsion to gamble; they do nothing to stop the neurodegeneration.

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Rather than replacing the missing dopamine, scientists led by Karolinskas Ernest Arenas tried to replace dopamine neurons but not in the way that researchers have been trying since the late 1980s. In that approach, scientists obtained tissue containing dopamine neurons from first-trimester aborted fetuses and implanted it intopatients brains.Although a 2001clinical trialfound that the transplants partly alleviated the rigidity and tremors of Parkinsons, the procedure caused serious dyskinesia in about 20 percent of patients, Beck said. More problematic is that fetal issue raises ethical concerns and is in short supply.

It was clear that usable fragments of brain tissue were extremely difficult to recover, said Dr. Curt Freed, of the University of Colorado, who pioneered that work.

Instead, several labs have therefore used stem cells to produce dopamine neurons in dishes. Transplanted into the brains of lab rats with Parkinsons, the neurons reduced rigidity, tremor, and other symptoms. Human studies are expected to begin in the US and Japan this year or next, Beck said.

In the Karolinska approach, there is no need to search for donor cells and no cell transplantation or [need for] immunosuppression to prevent rejection, Arenas told STAT. Instead, he and his team exploited one of the most startling recent discoveries in cell biology: that certain molecules can cause one kind of specialized cell, such as a skin cell, to pull a Benjamin Button, aging in reverse until they become like the embryonic cells called stem cells. Those can be induced to morph into any kind of cell heart, skin, muscle, and more in the body.

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Arenas and his team filled harmless lentiviruses with a cocktail of four such molecules. Injected into the brains of mice with Parkinsons-like damage, the viruses infected plentifulbrain cells called astrocytes. (The brains support cells, astrocytes perform jobs like controlling blood flow.)The viruses also infected other kinds of cells, but their payload was designed to work only in astrocytes, and apparently caused no harm to the other cells.

The molecules, called transcription factors, reprogrammed some of the astrocytes to become dopamine neurons, which were first detected three weeks later in the mouse brains. The dopamine neurons were abundant 15 weeks later, an indication that after changing into dopamine neurons the astrocytes stayed changed.

Five weeks after receiving the injections, the mice, which used to have Parkinsons-like gait abnormalities, walked as well as healthy mice. That suggests that direct reprogramming [of brain cells] has the potential to become a novel therapeutic approach for Parkinsons, Arenas told STAT.

That could have value for preserving the brain circuitry destroyed by Parkinsons, said Colorados Freed.

A lot of hurdles need to be overcome before this becomes a Parkinsons treatment. The Trojan horse system for delivering the reprogramming molecules inside viruseswould need to turn more astrocytes into dopamine neurons and leave other kinds of cells alone: Although viruses getting into mouse brain cells apparently caused no harm, that might not be so in people. We will need to use virus with selective [attraction] for astrocytes, Arenas said.

The morphed cells would presumably be ravaged by whatever produced Parkinsons in the first place. But in other cell transplants, Arenas said, the disease catches up with transplanted cells in 15 to 20 years, buying patients a good period of time. He thinks it might be possible to give patients a single injection but hold off some of the reprogramming with a drug, turning it on when the brain again runs short of dopamine neurons.

The basic technology to develop such strategies currently exists, he said.

The Karolinska lab is working to make the techniquesafer and more effective, including by using viruses that would deliver reprogramming molecules only to astrocytes. We are open to collaborations aimed at human studies, Arenas said.

Would patients be willing to undergo brain injections? People with Parkinsons disease, Beck said, are willing to go through a lot for any hope of improvement.

Sharon Begley can be reached at sharon.begley@statnews.com Follow Sharon on Twitter @sxbegle

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Mighty morphed brain cells cure Parkinson's in mice, but human trials still far off - STAT