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Engineered Stem Cells Could Be Next Parkinson’s Treatment, Researchers Say

gene editing

Cutting out a portion of or removing a gene linked to Parkinson’s disease protects against the formation of toxic protein clumps within brain cells, scientists have found.

This discovery has the potential to significantly affect the development of next-generation cell-based therapies, which involve injecting healthy cells into brain regions already affected by the disease. Researchers believe the approach may help relieve motor symptoms such as tremor and balance issues.

Findings were published in the study, “Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene,” in the European Journal of Neuroscience. The work was funded by the U.K. Centre for Mammalian Synthetic Biology, UCB, and The Cure Parkinson’s Trust.

Mutations in the SNCA gene have been found to cause Parkinson’s, a condition characterized by the selective death of midbrain dopamine-producing neurons due to clustering of a protein called alpha-synuclein, also known as Lewy bodies.

Transplantation of dopamine-producing neurons has proved useful in disease management because it can reinnervate Parkinson’s-affected brain regions, restore dopamine levels, and provide symptom relief.

Clinical studies on the transplant of fetal mesencephalic (meaning “of or relating to the midbrain”) tissue into the striatum — a critical area of the brain involved in Parkinson’s — have shown that although some patients saw their motor symptoms improved, others had transplant-induced dyskinesias — abnormal, uncontrolled, and involuntary movement.

Importantly, transplanted tissue (grafts) older than 10 years developed Lewy bodies, which reduced the symptomatic benefit to the patient.

“These clinical observations highlight the need for cell therapies that are resistant to the formation of Lewy bodies. … Such disease-resistant cells will be particularly important for patients with young-onset Parkinson’s or genetic forms of the condition with substantial alpha-synuclein burden,” the researchers wrote.

The team used a gene editing tool known as CRISPR-Cas9. This technique allows scientists to edit parts of the genome by removing, adding, or altering specific sections of the DNA sequence.

Using stem cells, researchers created two distinct cell lines: one with snipped-out portions of the SNCA gene and another without the SNCA gene.

These stem cells were then transformed into dopamine-producing neurons and treated with a chemical agent (recombinant alpha-synuclein pre-formed fibrils) to induce the formation of Parkinson’s-related Lewy bodies.

The team reported that wild-type neurons, or unedited brain cells, were fully susceptible to the formation of toxic aggregates, while engineered cells were significantly resistant to Lewy body formation.

“We know that Parkinson’s disease spreads from neuron [to] neuron, invading healthy cells. This could essentially put a shelf life on the potential of cell replacement therapy. Our exciting discovery has the potential to considerably improve these emerging treatments,” Tilo Kunath, PhD, group leader at the Medical Research Council’s Centre for Regenerative Medicine, University of Edinburgh, and senior author of the study, said in a press release.

By finding a way to “shield” cells from Parkinson’s molecular changes, scientists may have opened the door to the development of cell therapies capable of diverting time’s negative effect on transplanted tissue.

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New Purification Method May Improve Stem Cell Replacement Therapy for Parkinson’s

Stem Cell Purification Method

A new process to select and purify stem cells that hold therapeutic potential to replace dopamine-producing neurons may hasten clinical development of this promising avenue to treat Parkinson’s disease.

Upon being transplanted, these cells promoted dopamine production and reduced the severity of disease-related motor symptoms in an animal model of Parkinson’s disease.

The pre-clinical study with that finding, “Discovery of Novel Cell Surface Markers for Purification of Embryonic Dopamine progenitors for Transplantation in Parkinson’s Disease Animal Models,” was published in Molecular & Cellular Proteomics.

Current standard therapies for Parkinson’s disease focus mainly on restoring dopamine signaling in the brain to reduce the severity of symptoms and improve patients’ quality of life. However, this strategy does not resolve the main mechanism that leads to dopamine reduction — the loss of a specific population of brain cells called dopaminergic neurons.

In recent years the transplant of stem cells (a type of cell that can give rise to almost any cell type in the body) that can replace dopamine-producing neurons has become an attractive therapeutic pathway. But its translation into the clinics has been delayed, in part, due to the difficulty to select and purify stem cells that hold therapeutic potential without contamination of unwanted progenitor cells that could lead to tumors  and other complications.

“Although robust methods have been introduced that produce enough modified cells, uncertainty remains for selecting the right cell types from human pluripotent cells for transplantation,” researchers wrote.

Researchers now have developed a new standardized method that can ease the selection and purification of stem cells that specifically differentiate into dopamine-producing nerve cells, which are those affected in Parkinson’s disease.

The team engineered human stem cells to produce a green florescent protein that could be detected easily, as well as the LMX1A protein, which is an important marker of dopaminergic progenitors during brain cell differentiation.

These stem cells were cultured for 12 days in the laboratory and transformed into the desired mature dopamine-producing neurons. In undifferentiated cells, the fluorescent reporter was not produced.

The team further isolated their cells of interest based on the presence of a surface protein, called contactin 2 (CNTN2), which also is a characteristic marker of dopaminergic brain cell progenitors.

To test their activity, researchers transplanted these purified cells into the brains of rats with Parkinson’s disease, and compared the animals’ outcomes with those transplanted with unpurified stem cell-derived cells, or those left untreated.

Both groups of treated rats showed significant symptom improvement after 10 weeks of receiving the cells. Still, the rats that received CNTN2-enriched cells — produced and isolated using the new method — had a faster motor recovery and better dopamine production.

Researchers believe these results demonstrate that “purity of transplanted cells might be a more critical parameter to achieve recovery of motor abilities compared to the number of transplanted cells.”

Given that, the newly established purification method can be an efficient approach to produce large numbers of human stem cell-derived “dopaminergic progenitors for therapeutic applications,” they added.

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Source: Parkinson's News Today