Designer neurons offer new hope in the treatment of Parkinson’s disease

Summary: Researchers have developed a new way to transform non-nervous cells into neurons capable of forming synapses, releasing dopamine, and restoring the function of neurons damaged by Parkinson’s destruction of dopaminergic cells.

A source: Arizona State University

Neurodegenerative diseases damage neurons and damage mental and physical health. Parkinson’s disease, which affects more than 10 million people worldwide, is no exception. The most obvious symptoms of Parkinson’s disease occur after the disease has damaged a specific class of neurons in the midbrain. Its effects deprive the brain of dopamine, the main neurotransmitter produced by damaged neurons.

In a new study, Jeffrey Cordower and his colleagues transform non-neuronal cells into neurons that can be located in the brain, send their fibrous branches to working neurons, form synapses, release dopamine, and restore Parkinson’s disease-damaged neurons. destruction of dopaminergic cells.

Evidence-based research into the current concept has shown that when a group of experimentally developed cells are implanted in the rat’s brain, they can function optimally in terms of life, growth, neuronal connections and dopamine production.

Studies show that the results of such neuron transplants effectively eliminate the motor symptoms associated with Parkinson’s disease.

Stem cell replacement therapy represents a radical new strategy for the treatment of Parkinson’s and other neurodegenerative diseases. The futuristic method will soon be tested in the first clinical trial in a specific population affected by Parkinson’s disease with a mutation in the Parkin gene.

The trial is being held at various locations, including the Barrow Neurological Institute in Phoenix, with Cordower as chief investigator.

“We are not happy to be able to help people with a genetic form of Parkinson’s disease, but the lessons learned from this test have a direct impact on patients with sporadic or non-genetic forms of the disease,” Cordower says.

Cordower heads the ASU-Banner Neurodegenerative Diseases Research Center at Arizona State University and is a graduate of the Institute of Biodesign with Charlene and J.S. Dear Director of Orin Edson. The new study details the experimental preparation of stem cells for implantation to overcome the effects of Parkinson’s disease.

The study was published in the current issue of the journal Natural Rehabilitation Medicine.

New Perspectives on Parkinson’s Disease

You don’t have to be a neurologist to diagnose a neuron. These cells are immediately recognizable by their branched arches of axons and dendrites, and unlike any other cell type in the body. They use electrical impulses to monitor the heartbeat and speech. Neurons are also the custodians of our hopes and anxieties, the source of our personalities.

Disruption and loss of dopaminergic neurons cause symptoms of physical stiffness, tremor, and instability that characterize Parkinson’s disease. Side effects of Parkinson’s disease can include depression, anxiety, memory loss, hallucinations, and dementia.

As the population ages, humanity is facing a growing crisis in the number of people with Parkinson’s disease, which by 2040 will exceed 14 million worldwide. Current therapies, including the use of L-DOPA, can only solve some problems. The motor symptoms of the disease can cause serious, often unbearable side effects after 5-10 years of use.

There is no cure that can cure Parkinson’s disease or stop it from developing. Long-range innovations are needed to address this pending emergency.

A powerful weapon against Parkinson’s (pleurisy)

Despite the intuitive attractiveness of simply replacing dead or damaged cells to treat neurodegenerative disease, successful implantation of viable neurons to restore function is challenging. Researchers, including Cordower, had to overcome many technical barriers to achieve positive results using a class of cells called stem cells.

After 2012, John B. After Gurdon and Shinya Yamanaka shared the Nobel Prize for their achievements in the study of stem cells, interest in stem cells as a favorable therapy for a number of diseases grew rapidly.

They have shown that they are able to reprogram mature cells, make them “pluripotent,” or differentiate them into any type of cell in the body.

These pluripotent stem cells flourish during embryonic development, migrate to their habitat, and undergo one of the most significant changes in nature: the heart, nerves, lungs, and other cell types.

neuron alchemy

There are two types of large cells. One type is found in fully developed tissues such as bone marrow, liver and skin. These stem cells are small in number and often become the type of cells that belong to the tissues from which they are derived.

The second type of adult (and the purpose of this study) is known as induced pluripotent cells (iPSCs). The iPSC production techniques used in the study are in two stages. In other words, the cells first travel backwards and then forwards.

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

Studies show that the results of such neuron transplants effectively eliminate the motor symptoms associated with Parkinson’s disease. Image in public domain

“The main conclusion of this paper is that the timing of the second set of factors is crucial,” Cordower said. “If you treat them for 17 days, make them cultured, and then stop the separation and differentiate, that’s best.”

Perfect neurons

The experiments included iPSCs grown for 24 and 37 days, but those grown for 17 days before differentiation into dopaminergic neurons were significantly higher, with a large number of survivors able to send their branches over long distances.

“It’s important,” says Cordower, “because they have to grow long distances in the larger human brain, and we now know that these cells can do that.”

Rats treated with 17-day iPSCs were miraculously cured of the motor symptoms of Parkinson’s disease. Further research shows that this effect is dose-dependent.

When a small number of iPSCs are implanted in the brains of animals, recovery is negligible, but most of the cells completely eliminate nerve branching and Parkinson’s symptoms.

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It shows a couple sitting in front of a TV

The first clinical trial used iPSC therapy in a group of patients with Parkinson’s who had a specific genetic mutation known as Parkin’s mutation. Such patients suffer from the typical symptoms of motor dysfunction found in general or idiopathic Parkinson’s, but do not suffer from cognitive decline or dementia.

This cohort of patients provides the ideal test for cell replacement therapy. If the treatment is effective, there will be major tests to apply the strategy to the version of Parkinson’s patients.

In addition, treatment can be combined with therapies used to treat Parkinson’s disease. Once dopamine-producing substitute cells are implanted in the brain, lower doses of drugs such as L-DOPA can be used to alleviate side effects and improve outcomes.

Research has shown that damaged or dead neurons can be replaced with new cells.

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

Research on Parkinson’s disease

Author: Press service
A source: Arizona State University
The connection: Press Service – Arizona State University
Photo: Image in public domain

Original study: Open access.
“Optimizing the maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease” Benjamin M. Hiller et al. Natural Rehabilitation Medicine


Abstract

Optimizing the maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease

Differentiated pluripotent stem cells (iPSC) are an ideal source of dopaminergic (mDA) cells in the midbrain, seeking to treat Parkinson’s disease with cell replacement therapy. We previously developed a protocol to differentiate post-mitotic mDA neurons derived from iPSC capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats.

In this study, we identified a differentiation protocol adapted for transferring iPSC source material and then transferring to clinical cell transplantation therapy.

We found that mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) were effective in influencing cell survival and transplantation in immunocompromised hemiparkinsonian rats.

We found that D17 progenitors were significantly superior to immature D24 or mature D37 neurons in terms of survival, fiber proliferation, and effects on motor deficits. Intranigral transplantation into the ventral midbrain has shown that D17 cells have the ability to innervate long-distance brain structures, including the striatum, more than D24 cells.

When D17 cells were evaluated over a wide dose range (7,500-450,000 injected cells per striatum), there was an accurate dose response to the number of surviving neurons, innervation, and functional recovery. Importantly, although these transplants were derived from iPSCs, we did not observe a significant increase in the formation of teratomas or other cells in any other animal.

These data support the notion that human iPSC-derived D17 mDA progenitors are suitable for clinical development to test transplantation in patients with Parkinson’s disease.

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