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Designer neurons bring hope for treatment of Parkinson’s disease

Such neural grafts can effectively reverse motor symptoms due to the disease.

It is known that neurodegenerative diseases like Parkinson's, which affects over 10 million people worldwide, damage and destroy neurons, causing damage to the sufferer's mental and physical health.

Parkinson's is caused by the gradual damage or death of dopamine-producing neurons in a part of the brain called the substantia nigra. The reduction in dopamine results in the onset of symptoms, which may include rigidity, tremors, slowed movement, loss of autonomic function, changes in speech, and postural instability. Symptoms tens to start gradually and worsen over time.

Additional effects of Parkinson's disease can include depression, anxiety, memory deficit, hallucinations, and dementia.

Researchers believe the underlying cause of Parkinson's may be a combination of genetic, environmental, and lifestyle factors. Parkinson's disease cases are expected to number more than 14 million globally by 2040, an increase driven partly by an aging population. Current treatments, which include the use of the drug L-DOPA, as well as dopamine agonists and/or monoamine oxidase-B inhibitors. These drugs help to increase dopamine levels in the brain but are only able to address some of the symptoms of the disease, and do not halt its progression. They may also produce serious, often intolerable side effects after many years of use.

There's good news, though.

A radical strategy

Stem cell replacement therapy, or regenerative medicine, could open up a radical new path for the treatment of Parkinson's and other neurodegenerative diseases. 

Thepioneering approach will soon be put to the test in the first of its kind clinical trial, in a specific population of people living with a form of Parkinson’s disease caused by a mutation in the PRKN (parkin) gene. 

The research was published in the current issue of the Nature Partner Journals (npj) publication Nature Regenerative Medicine.

“We cannot be more excited by the opportunity to help individuals who suffer from this genetic form of Parkinson’s disease, but the lessons learned from this trial will also directly impact patients who suffer from sporadic, or non-genetic forms of this disease,” said Jeffrey Kordower, founding director of the ASU-Banner Neurodegenerative Disease Research Center and endowed chair as The Charlene and J. Orin Edson Distinguished Director at the Biodesign Institute at Arizona State University.

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The result could reverse motor symptoms

The trial will be conducted at various locations, including the Barrow Neurological Institute in Phoenix, with Kordower as the principal investigator.

In the research, Kordower and his colleagues describe a process to convert non-neuronal stem cells into functioning neurons, and then transplanting these neurons to the brain, via neural grafting, in which stem cells are directly implanted in the brain.

Kordower and others have already demonstrated that such implanted cells can develop into functional neurons in rats, releasing dopamine and restoring capacities undermined by Parkinson's destruction of dopaminergic cells.

The current study reveals that one group of experimentally engineered cells performs optimally in terms of survival, growth, neural connectivity, and dopamine production when implanted in the brains of rats.

The study demonstrates that the result of such neural grafts is to effectively reverse motor symptoms due to Parkinson’s disease.

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Stem cell replacement therapy
The new study describes the implantation of induced pluripotent stem cells (iPSCs) to replace dopamine-producing neurons destroyed by Parkinson's disease. Source: Shireen Dooling/Biodesign Institute at Arizona State University

How does it work?

It's not all that easy, though.

Adult stem cells come in two varieties. One type can be found in fully developed tissues like bone marrow, liver, and skin. The second kind of adult stem cells - the focus of this study - are known as induced pluripotent stem cells (iPSCs).

The technique for producing the iPSCs used in the study takes place in two phases.

First, adult blood cells are treated with specific reprogramming factors that cause them to revert to embryonic stem cells. The second phase treats these embryonic stem cells with additional factors, causing them to differentiate into the desired target cells—dopamine-producing neurons.

“The major finding in the present paper is that the timing in which you give the second set of factors is critical,” Kordower says. “If you treat and culture them for 17 days, and then stop their divisions and differentiate them, that works best.”

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Can we expect a complete reversal?

Rats treated with the 17-day iPSCs showed remarkable recovery from the motor symptoms of Parkinson’s disease. The study further demonstrated that this effect is dependent on the dose.

When a small number of iPSCs were grafted into the animal brain, recovery was negligible, but a large complement of cells produced more profuse neural branching, and complete reversal of Parkinson’s symptoms.

The initial clinical trial will apply iPSC therapy to a group of Parkinson’s patients bearing a particular genetic mutation in the PKRN gene. 

Larger trials will follow if the treatment is effective.

Once effective, a useful tool to treat a wide range of diseases

The treatment could also potentially be combined with existing therapies to treat Parkinson’s disease. Once the brain has been seeded with dopamine-producing replacement cells, lower doses of drugs like L-DOPA could be used, enhancing beneficial results and mitigating side effects.

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Such research sets the stage for the replacement of damaged or dead neurons with fresh cells for a broad range of devastating diseases.

“Patients with Huntington's disease or multiple system atrophy or even Alzheimer’s disease could be treated in this way for specific aspects of the disease process,” said Kordower.

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