Engineering neurons offer new hope for treatment of Parkinson’s disease – Neuroscience News


Summary: Researchers have devised a novel method of converting non-neural cells into functional neurons capable of forming synapses, delivering dopamine and restoring neuron function undermined by the dopamine cell destruction associated with Parkinson’s disease.

Source: Arizona State University

Neurodegenerative diseases damage and destroy neurons, ravaging both 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 located in the midbrain. The effect is to deprive the brain of dopamine, a key neurotransmitter produced by affected neurons.

In new research, Jeffrey Kordower and his colleagues describe a process of converting non-neuronal cells into functional neurons capable of taking up residence in the brain, sending their fibrous branches through neural tissue, forming synapses, distributing dopamine and restore capacities undermined by Parkinson’s disease. destruction of dopaminergic cells.

The current proof-of-concept study reveals that a group of experimentally designed cells perform optimally in terms of survival, growth, neuronal connectivity and dopamine production, when implanted in the brains of rats.

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

Stem cell replacement therapy represents a radical new strategy for the treatment of Parkinson’s disease and other neurodegenerative diseases. The futuristic approach will soon be tested in the first clinical trial of its kind, in a specific population of people with Parkinson’s disease who carry a mutation in the parkin gene.

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

“We couldn’t be more excited about the opportunity to help people who suffer from this genetic form of Parkinson’s disease, but the lessons learned from this trial will also have a direct impact on patients who suffer from sporadic or non-genetic factors of this disease,” Kordower said. said.

Kordower directs the ASU-Banner Center for Neurodegenerative Disease Research at Arizona State University and is Charlene and J. Orin Edson’s Director Emeritus at the Biodesign Institute. The new study details the experimental preparation of stem cells suitable for implantation to reverse the effects of Parkinson’s disease.

The search appears in the current issue of the journal Natural regenerative medicine.

New insights into Parkinson’s disease

You don’t have to be a neuroscientist to identify a neuron. These cells, with their branching tree of axons and dendrites, are instantly recognizable and unlike any other type of cell in the body. Through their electrical impulses, they exercise meticulous control over everything from heartbeat to speech. Neurons are also the repository of our hopes and anxieties, the source of our individual identity.

The degeneration and loss of dopaminergic neurons cause the physical symptoms of rigidity, tremor and postural instability that characterize Parkinson’s disease. Other effects of Parkinson’s disease can include depression, anxiety, memory deficit, hallucinations, and dementia.

Due to the aging of the population, humanity is facing a growing crisis of cases of Parkinson’s disease, the number of which is expected to reach more than 14 million worldwide by 2040. Current therapies, which include the use of the drug L-DOPA, can only treat some of the motor symptoms of the disease and can produce serious side effects, often intolerable after 5 to 10 years of use.

There is no treatment that can reverse Parkinson’s disease or halt its relentless progression. Far-sighted innovations to address this looming emergency are desperately needed.

A (multi)powerful weapon against Parkinson’s disease

Despite the intuitive appeal of simply replacing dead or damaged cells to treat neurodegenerative diseases, the challenges to successfully implant viable neurons to restore function are formidable. Many technical hurdles had to be overcome before researchers, including Kordower, could begin to achieve positive results, using a class of cells called stem cells.

Interest in stem cells as an attractive therapy for a range of diseases quickly gained momentum after 2012, when John B. Gurdon and Shinya Yamanaka shared the Nobel Prize for their breakthrough in stem cell research. .

They showed that mature cells can be reprogrammed, making them ‘pluripotent’ – or able to differentiate into any type of cell in the body.

These pluripotent stem cells are functionally equivalent to fetal stem cells, which flourish during embryonic development, migrating to their place of residence and developing into heart, nerve, lung and other cells, in one of the most remarkable transformations of nature.

Neuronal alchemy

Adult stem cells come in two varieties. One type can be found in fully developed tissues like bone marrow, liver, and skin. These stem cells are few in number and usually develop into the type of cells belonging to the tissue from which they originate.

The second type of adult stem cells (and the focus of this study) is known as induced pluripotent stem cells (iPSCs). The iPSC production technique used in the study takes place in two phases. In a way, the cells are made to travel in time, first in the opposite direction and then in the opposite direction.

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

The study demonstrates that the result of such neural transplants is to effectively reverse motor symptoms due to Parkinson’s disease. Image is in public domain

“The main takeaway from this paper is that the timing of when you give the second set of factors is critical,” Kordower says. “If you treat them and culture them for 17 days, then stop their divisions and differentiate them, it works better.”

Launch perfect neurons

The study experiments included iPSCs cultured for 24 and 37 days, but those cultured for 17 days before differentiation into dopaminergic neurons were markedly superior, able to survive in greater numbers and send their branches long distances.

“That’s important,” Kordower says, “because they’re going to have to grow long distances into the larger human brain and we now know that these cells are able to do that.”

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

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

See also

It shows a couple sitting in front of the TV

The initial clinical trial will apply iPSC therapy to a group of patients with Parkinson’s disease who carry a particular genetic mutation, known as the Parkin mutation. These patients suffer from the typical symptoms of motor dysfunction seen in general or idiopathic Parkinson’s disease, but do not suffer from cognitive decline or dementia.

This cohort of patients provides an ideal testing ground for cell replacement therapy. If the treatment is effective, larger trials will follow, applying the strategy to the version of Parkinson’s disease that affects most patients with the disease.

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

Research is laying the groundwork for replacing damaged or dead neurons with fresh cells for a wide 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,” Kordower says.

About this Parkinson’s disease research news

Author: Press office
Source: Arizona State University
Contact: Press Office – Arizona State University
Picture: Image is in public domain

Original research: Free access.
“Maturity and dose optimization of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease” by Benjamin M. Hiller et al. Natural regenerative medicine


Abstract

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

In further treatment of Parkinson’s disease with cell replacement therapy, induced differentiated pluripotent stem cells (iPSCs) are an ideal source of midbrain dopamine (mDA) cells. We have previously established a protocol to differentiate post-mitotic iPSC-derived mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats.

In the present study, we transitioned the iPSC starting material and defined a suitable differentiation protocol for further translation into clinical cell transplantation therapy.

We examined the effects of cell maturity on the survival and efficiency of grafts by grafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24) and post-mitotic neurons (D37) in immunocompromised hemiparkinsonian rats.

We found that D17 progenitors were significantly superior to immature D24 or mature D37 neurons in terms of survival, fiber growth, and effects on motor deficits. Intranigral grafting to the ventral midbrain demonstrated that D17 cells have a greater ability than D24 cells to innervate forebrain structures, including the striatum, over long distances.

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

These data support the concept that human iPSC-derived D17 mDA progenitors are suitable for clinical development for the purpose of transplantation trials in patients with Parkinson’s disease.


Leave a Reply

Your email address will not be published.