New Way of Manipulating Stem Cells Leads to Healthy Nerve Cells in Animal Study

stem cell study

Scientists have created a special matrix that allowed them to differentiate stem cells into nerve cells that, when transplanted into a rat model of Parkinson’s disease, eased the animals’ symptoms by replacing those nerve cells lost to the disease.

This matrix is also able to stimulate differentiation of stem cells, prodding them to become nerve cells, without a need for growth factors thought to raise a cancer risk in treated patients.

Their study, “Extracellular Nanomatrix‐Induced Self‐Organization of Neural Stem Cells into Miniature Substantia Nigra‐Like Structures with Therapeutic Effects on Parkinsonian Rats,” was published in the journal Advanced Science.

Parkinson’s is characterized by the gradual loss of dopamine-producing nerve cells in the substantia nigra, a region of the brain responsible for movement control.

Stem cell therapy — which involves growing and differentiating stem cells into specific types of cells — is among the most promising of those treatments seeking to cure Parkinson’s, due to its potential to replace dopaminergic nerve cells lost in the course of the disease.

However, its potential has been hindered by a series of technical challenges, including the type and large number of materials (e.g., growth factors) required, the long time period necessary, and a low efficiency.

The use of growth factors to promote stem cell differentiation is particularly troubling, as these factors may also stimulate the growth of cancer cells after a transplant.

“Currently, an effective method to induce the rapid and specific differentiation of [stem cells] into [nerve cells] without applying traditional GFs [growth factors] is lacking. Such a method is urgently needed to enable the development of [stem cell] therapies that may ultimately cure PD [Parkinson’s disease],” the researchers wrote.

A team at Hong Kong Baptist University (HKBU) created a special matrix material that can stimulate the growth and differentiation of nerve cell progenitors into miniature substantia nigra-like structures, or mini-SNLSs. These mini-SNLSs contain the dopamine-producing nerve cells that are lost to Parkinson’s.

Their new nanomatrix does not require that stem cells be stimulated with growth factors in order to get them to differentiate into dopamine-producing nerve cells.

Instead, the nanomatrix uses trillions of biocompatible silica “nanozigzag” structures on its surface to stimulate stem cells and promote their differentiation.

“When the neural stem cells come into physical contact with our tailor-made nanozigzag matrix in vitro, the ‘physical massage’ can induce the cells to differentiate rapidly into the desired dopaminergic neurons,” Jeffery Huang Zhifeng, associate professor of the Department of Physics at HKBU, and study co-author, said in a press release.

“A self-organized mini-brain-like structure can be developed in only two weeks with risk of carcinogenesis substantially reduced,” Zhifeng added.

After generating mini-SNLSs using the new nanomatrix, the investigators tested how their functionality and therapeutic potential in a rat model of Parkinson’s.

They transplanted the mini-SNLSs they created into the brain of animals whose severe motor impairments mimicked those of Parkinson’s.

Eight weeks later, all transplanted animals started showing progressive improvements in their motor abilities. After 18 weeks, researchers found that newly differentiated, dopamine-producing nerve cells had started to spread around the transplant site, replacing those cells the animals had lost over the course of the disease.

The study noted that first evidence of improvement was seen at 16 weeks post-transplant in previous stem cell work in Parkinson’s animal models, while “motor symptom amelioration was initiated at a much earlier time point following the transplantation of neurons from the mini‐SNLSs.”

No evidence of cancer or tumor formation was found in any of the animals after the transplant. Rats in this model not given a transplant, and used as controls, never showed any signs of motor improvement.

“The results showed that these mini-brain-like structures exhibited excellent survival and functionality in the brains of rats and resulted in the early and progressive improvement of Parkinson’s disease in rats in vivo. It lays the foundation for research into stem cell therapies that may ultimately cure Parkinson’s disease,” Zhifeng said.

This nanomatrix may be used to differentiate stem cells into other cell types, by altering the stiffness, density, and structure of the nanozigzags on its surface, the team added. And it may aid in treatment development for other incurable disorders, such as Alzheimer’s disease and some types of cancer.

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Treating Stem Cells with Fasudil Eases Parkinson’s Symptoms in Mouse Model, Study Finds

mouse stem cell study

Bone marrow stem cells treated with fasudil and administered via the nose (intranasal) to mice in a model of Parkinson’s disease led to evidence of better motor abilities and a reduced of dopaminergic neurons,  a recent study from China reports.

These results suggest that fasudil’s use and intranasal delivery could lead to better stem cells treatments for Parkinson’s.

The research, “Intranasal Delivery of Bone Marrow Stromal Cells Preconditioned with Fasudil to Treat a Mouse Model of Parkinson’s Disease,” was published in Dove Press.

Stem cell therapy is a promising approach for various illnesses, but getting cells into the brain is a challenge. Current techniques like intravenous (IV) injection either fail to cross the blood brain barrier (BBB), while others are highly invasive, as with intraventricular injections (directly into the brain). The BBB, a semipermeable membrane that’s essential in protecting the brain from blood-borne threats like viruses, can also prevent treatments from reaching the brain and central nervous system — areas they need to reach to work as intended.

To understand whether a different route of stem cell administration would be more effective, researchers at Fudan University in Shanghai used bone marrow stromal cells (BMSCs). BMSCs are those stem cells derived from bone marrow that can differentiate into several types of cells, including neural cells.

These cells were delivered through the nose to mice engineered to develop symptoms that mimic Parkinson’s. Three experimental groups were treated: mice given intranasal administration of unconditioned BMSCs, those given BMSCs treated with fasudil, and those given BMSCs conditioned with an inert liquid called PBS, commonly used as an experimental control.

Fasudil belongs a class of molecules that enhances the growth and differentiation of stem cells, and has been shown to improve their ability to be grafted onto new tissue and survive transplantation. It is used in China and Japan to treat cerebral vasospasm (hemorrhage) and some types of stroke, but is not approved in the U.S. or Europe.

Unconditioned and fasudil-conditioned BMSCs migrated to the substantia nigra and olfactory bulbs within the animals’ brains. Dopamine-producing (dopaminergic) neurons die in both of these structures during Parkinson’s, contributing to disease progression.

Fasudil-conditioned stem cells effectively prevented dopaminergic neuron loss within the substantia nigra of treated mice, the researchers reported. This benefit was not observed in the other experimental groups.

Mere survival of dopaminergic neurons would do little to improve Parkinson’s symptoms without also making and releasing dopamine: a neurotransmitter essential for muscle and mood control. Mice treated with fasudil-BMSCs showed higher concentrations of dopamine and its metabolites, and a greater neurotransmitter release than either of the other two groups.

Fasudil-BMSC treatment also significantly reduced neuroinflammation and increased the release of BDNF, a signaling molecule important to neuronal cell survival. Neuroinflammation has been implicated in the progression of Parkinson’s disease, and controlling it eases many of its symptoms.

Behaviorally, mice given fasudil-treated BMSCs also had better scores on the Rotarod test, a common laboratory measure of motor function. In contrast, mice in the PBS control and the unconditioned stem cell groups showed no improvements in motor abilities.

Exactly how BMSCs travel from the nasal passages to the brain is not yet understood. But this study provides further evidence that such travel takes place, and treating cells with fasudil may be beneficial.

Its results also support fasudil-treated BMSCs being useful in several areas of future Parkinson’s therapy, including enhancing the survival of functional dopaminergic neurons, and suppressing immune and inflammatory responses.

If proven to work well in further studies, intranasal stem cell administration (perhaps through a spray) could be a convenient and non-invasive way of delivering stem cell therapy.

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Aspen Neuroscience Receives $6.5M to Advance New Patient-specific Cell Therapy for Parkinson’s

Aspen Neuroscience

Aspen Neuroscience, a new biotech company, has raised $6.5 million to develop cell therapies for Parkinson’s disease using patients’ own cells.

The company was co-founded by renowned stem cell scientists Jeanne F. Loring, PhD, and Andres Bratt-Leal, PhD, and initially supported by Summit for Stem Cell, a non-profit organization that provides a variety of services for Parkinson’s patients.

Parkinson’s hallmark motor symptoms include tremor, slowness of movement (bradykinesia), stiffness (rigidity), uncontrollable movements (dyskinesia), and poor balance.

As the disease progresses, patients typically need to gradually increase their dopaminergic therapeutic dose for maximum benefit. Even after that they might sometimes experience reappearance or worsening of symptoms due to diminishing effects of dopaminergic therapy, known was “off” periods.

Importantly, dopaminergic therapy is delivered to areas of the brain other than the striatum, a key motor control region severely affected in Parkinson’s disease. Because of the therapy’s off-target behavior, patients also may experience side effects such as hallucinations or cognitive impairment.

Aspen wants to combine its expertise in stem cell biology, genomics and neurology and develop the first autologous (self) stem cell-based therapy for Parkinson’s disease.

In this type of cell therapy, a patient’s own cells (usually skin cells) are reprogrammed back into a stem cell-like state, which allows the development of an unlimited source of almost any type of human cell needed, including dopamine-producing neurons, which are those mainly affected by this disorder.

Because these cells are derived from patients, they do not carry the risk of being rejected once re-implanted, eliminating the need for immunosuppressive complementary therapies, which carry serious side effects such as infections and possibly limiting therapeutic potential.

In theory, replacing lost dopaminergic neurons with new stem cell-derived dopamine-producing ones could potentially ease or reverse motor symptoms associated with the disease.

Aspen is developing a restorative, disease modifying autologous neuron therapy for people suffering from Parkinson’s disease,” Howard J. Federoff, MD, PhD, Aspen’s CEO, said in a press release.

“We are fortunate to have such a high-caliber scientific and medical leadership team to make our treatments a reality. Our cell replacement therapy, which originated in the laboratory of Dr. Jeanne Loring and was later supported by Summit for Stem Cell and its President, Ms. Jenifer Raub, has the potential to release dopamine and reconstruct neural networks where no disease-modifying therapies exist,” Federoff said.

The company’s lead product (ANPD001) is undergoing investigational new drug (IND)-enabling studies for the treatment of sporadic Parkinson’s disease. Aspen experts also are developing a gene-editing treatment (ANPD002) for familial forms of Parkinson’s, starting with the most common genetic variant in the GBA gene, which provides instructions to make the enzyme beta-glucocerebrosidase.

The new seed funding round was led by Domain Associates and Axon Ventures, with additional participation from Alexandria Venture Investments, Arch Venture Partners, OrbiMed and Section 32, according to the press release.

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For First Time, Precursors of Dopamine Neurons Implanted in Brain of Parkinson’s Patient

Parkinson's stem cells

Precursors of dopamine-producing cells were implanted into the brain of a Parkinson’s patient for the first time. The patient in Japan is the first of seven to receive this experimental therapy.

The approach uses induced pluripotent stem cells (iPSCs), which are developed by reprogramming cells collected from the skin or blood of adults so that they revert to a stem cell-like state and are able to differentiate into almost any cell type.

Scientists at Kyoto University can transform iPSCs into precursors of dopamine-producing neurons. In Parkinson’s, progressive loss of these neurons in a brain area called substantia nigra, and reduced dopamine release in a connected region called striatum, lead to the characteristic motor symptoms.

Last month, neurosurgeon Takayuki Kikuchi implanted 2.4 million dopamine precursor cells into the brain of a Parkinson’s patient in his 50s. The team implanted the cells into 12 centers of dopamine activity over three hours. Stem cell researcher Jun Takahashi and colleagues derived the dopamine precursor cells from iPSCs originally developed from skin cells of an anonymous donor.

“The patient is doing well and there have been no major adverse reactions so far,” Takahashi said in a Nature press release, written by David Cyranoski. The man will be observed over six months. If he does not develop complications, an additional 2.4 million dopamine precursor cells will be implanted into his brain.

Six more Parkinson’s patients are expected to receive this stem cell therapy, which will allow researchers to collect safety and efficacy data by the end of 2020. According to Takahashi, the treatment could reach the market as early as 2023 under Japan’s fast-track approval system for regenerative medicines. “Of course it depends on how good the results are,” he said.

In 2017, Takahashi and his team showed that dopamine-producing neurons transplanted into the brains of monkeys enabled them to move spontaneously over two years. Also, the transplanted cells did not lead to abnormal and jerky movements (dyskinesia), did not develop into tumors — a key concern with iPSCs-based treatments — and did not trigger an immune response not treatable with an immunosuppressive therapy.

In 2014, a Japanese woman in her 70s became the first patient to receive retinal cells derived from iPSCs to treat an eye condition called age-related macular degeneration.

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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