summary: Researchers have designed a new method to convert non-neuronal cells into functioning neurons capable of forming synapses, dispensing dopamine, and restoring the function of neurons impaired by Parkinson’s disease-related destruction of dopamine cells.
source: Arizona State University
Neurodegenerative diseases damage and destroy nerve cells, destroying 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 appear after the disease damages a specific class of neurons in the midbrain. The effect is to steal dopamine from the brain – a key neurotransmitter produced by injured neurons.
In new research, Jeffrey Cordor and colleagues describe the process of transforming non-neuronal cells into functioning neurons that are able to reside in the brain, send their fibrous branches through nerve tissue, form synapses, dispense dopamine, and restore abilities undermined by Parkinson’s disease. Destruction of dopamine cells.
The current proof-of-concept study reveals that a single set of experimentally engineered cells function optimally for survival, growth, neuronal connectivity and dopamine production, when transplanted into the brains of mice.
The study shows that the result of these nerve grafts is to effectively reverse the motor symptoms caused by Parkinson’s disease.
Stem cell replacement therapy represents a radical new strategy for treating Parkinson’s disease and other neurodegenerative diseases. The future approach will soon be tested in the first clinical trial of its kind, in a specific population of people with Parkinson’s disease that carries a mutation in the Parkin gene.
The experiment will be conducted at various locations, including the Barrow Neurological Institute in Phoenix, with Cordor as the principal investigator.
“We couldn’t be more excited about the opportunity to help individuals with this genetic form of Parkinson’s disease, but the lessons learned from this trial will also directly impact patients with sporadic or non-genetic forms of the disease,” Cordoer says.
Cordor directs the ASU-Banner Neurodegenerative Disease Research Center at Arizona State University and is the Charlene and J. Oren Edson Distinguished Director at the Biodesign Institute. The new study describes in detail the experimental preparation of stem cells suitable for transplantation to reverse the effects of Parkinson’s disease.
The research appears in the current issue of the journal Natural Regenerative Medicine.
New prospects for Parkinson’s disease
You don’t have to be a neuroscientist to identify neurons. Such cells, with their branching axons and dendrites, are recognizable and look unlike any other type of cell in the body. With their electrical impulses, they exert precise control over everything from heart rate to speech. Neurons are also the repository of our hopes and anxiety, and the source of our individual identity.
The degeneration and loss of dopaminergic neurons cause the physical symptoms of rigidity, tremors, and postural instability that are characteristic of Parkinson’s disease. Additional effects of Parkinson’s disease can include depression, anxiety, memory deficits, hallucinations, and dementia.
Due to an aging population, humanity is facing an escalating crisis of Parkinson’s disease cases, with the numbers expected to swell to more than 14 million by 2040. Current treatments, which include the use of L-DOPA, are only able to treat some of the motor symptoms of the disease and may result in Often unbearable serious side effects after 5-10 years of use.
No current treatment can reverse Parkinson’s disease or mercilessly stop its progression. Far-sighted innovations are urgently needed to address this outstanding emergency.
A powerful weapon against Parkinson’s disease
Despite the intuitive appeal of replacing dead or damaged cells for the treatment of neurodegenerative diseases, the challenges to successful transplantation of viable neurons to restore function are enormous. Several technical hurdles had to be overcome before researchers, including Cordur, could begin producing positive results, using a class of cells known as stem cells.
Interest in stem cells as an attractive treatment for a range of diseases gained rapid momentum after 2012, when John B.
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 embryonic stem cells, which thrive during embryonic development, migrate to their place of residence and develop into heart, nerves, lungs and other types of cells, in one of nature’s most remarkable transformations.
Adult stem cells come in two types. One type can be found in fully developed tissues such as bone marrow, liver, and skin. These stem cells are few in number and generally develop into the type of cells that belong to the tissues from which they are derived.
The second type of adult stem cell (and the focus of this study) is known as induced pluripotent stem cells (iPSCs). The iPSCs production technique used in the study occurs in two phases. Somehow, the cells are prompted to travel through time, at first, in the opposite direction and then forward.
First, the adult blood cells are treated with specific reprogramming factors that cause them to revert back to embryonic stem cells. The second stage treats these embryonic stem cells with additional factors, causing them to differentiate into the desired target cells – dopamine-producing neurons.
“The key finding in this paper is that the timing in which the second set of factors presents is critical,” Cordoer says. “If you deal with them and culture them for 17 days, and then stop their divisions and banding, that works better.”
The ideal pitch for neurons
The study experiments included iPSCs cultured for 24 and 37 days, but those cultured for 17 days before differentiating into dopaminergic neurons were significantly outperformed, able to survive in greater numbers and send their branches long distances.
“This is important, because they would have to grow long distances in the larger human brain, and we now know that these cells are able to do that,” Cordor says.
Mice treated with iPSCs for 17 days showed significant recovery from the motor symptoms of Parkinson’s disease. The study further demonstrates that this effect is dose dependent.
When a small number of iPSCs were grafted into the animal’s brain, recovery was minimal, but a large group of cells produced more prolific neuronal branching, a complete reversal of Parkinson’s symptoms.
The initial clinical trial will apply iPSC therapy to a group of Parkinson’s patients who carry a specific genetic mutation, known as a Parkin mutation. These patients have the typical symptoms of generally existing motor dysfunction or idiopathic Parkinson’s disease, but do not have cognitive decline or dementia.
This group of patients provides an ideal testing ground for cell replacement therapy. If treatment is effective, larger trials will be followed, applying the strategy to the version of Parkinson’s that affects most patients with the disease.
Furthermore, treatment can be combined with existing therapies to treat Parkinson’s disease. Once the replacement dopamine-producing cells have been implanted into the brain, lower doses of medications such as L-DOPA can be used, alleviating side effects, and promoting beneficial results.
The research paves the way for replacing damaged or dead neurons with new ones for a wide range of devastating diseases.
“Patients with Huntington’s disease, multiple system atrophy, or even Alzheimer’s disease can be treated in this way for specific aspects of the disease process,” Cordoer says.
About Research on Parkinson’s Disease
author: press office
source: Arizona State University
Contact: Press Office – Arizona State University
picture: The image is in the public domain
original search: open access.
“Maturation and dose optimization of dopamine-derived progenitor cell therapy for Parkinson’s disease” by Benjamin M. Heller et al. Natural Regenerative Medicine
Maturation and dose improvement of dopamine-derived progenitor cell therapy for Parkinson’s disease
In the pursuit of treating Parkinson’s disease through cell replacement therapy, induced differentiated stem cells (iPSC) are an ideal source of midbrain dopamine (MDA) cells. We previously established a protocol to differentiate iPSC-derived mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in mice.
In this study, we transfected the iPSC starting material and defined a differentiation protocol adapted for further translation into a clinical cell transplantation therapy.
We examined the effects of cellular maturation on the survival and efficacy of transplants by grafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) into immunocompromised mice.
We found that D17 progenitors were significantly superior to immature D24 neurons or mature D37 neurons in terms of survival, fiber growth and effects on motor deficits. Endocytosis in the ventral midbrain showed that D17 cells had a greater capacity than D24 cells to innervate over a long distance to forebrain structures, including the striatum.
When D17 cells were assessed over a wide dose range (7500–450,000 cells injected per scheme), there was a clear dose response regarding the number of neurons remaining, innervation, and functional recovery. Importantly, although these grafts are 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 with the aim of transplant trials in Parkinson’s patients.