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Parkinson’s May Originate From Alpha-Synuclein Migrating From the Gut, Rat Study Shows

gut Parkinson's alpha-synuclein

New experimental evidence collected from rats shows that alpha-synuclein — the protein that causes Parkinson’s disease — can travel from the intestines to other organs, such as the heart and brain.

These findings, reported in the study “Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats,” provide further support to the hypothesis that the development of Parkinson’s disease is directly linked to the intestinal system.

The study was published in Acta Neuropathologica.

A hallmark feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of alpha-synuclein, called Lewy bodies.

Prior work in postmortem human brains has shown that the misfolded protein primarily accumulates in brain areas controlling movement, which explains the characteristic motor symptoms associated with the disease. But that work also revealed the protein’s accumulation in the vagus nerve – which connects the brain to the gut.

This led to the theory that Parkinson’s progression could require communication between the gut and the brain.

To further explore this association, researchers from Aarhus University and its clinical center, in Denmark, conducted a new study in rats. The team used rats that were genetically modified to produce excessive amounts of alpha-synuclein, and which were susceptible to accumulating harmful versions of the protein in nerve cells. Human alpha-synuclein or an inactive placebo was injected into the small intestines of these rats.

With this approach, the investigators found that both groups of rats — those injected with alpha-synuclein or placebo — had high levels of the protein in the brain. However, only those injected with alpha synuclein showed Parkinson’s characteristic clump build-up patterns, which affected the motor nucleus and substantia nigra in the brain.

“After two months, we saw that the alpha-synuclein had travelled to the brain via the peripheral nerves with involvement of precisely those structures known to be affected in connection with Parkinson’s disease in humans,” Per Borghammer, an Aarhus University professor and the study’s senior author, said in a press release written by Mette Louise Ohana.

“After four months, the magnitude of the pathology was even greater. It was actually pretty striking to see how quickly it happened,” Borghammer said.

Alpha-synuclein also was found to accumulate in the heart and stomach, which suggests a secondary propagation pathway. That pathway likely is mediated by the celiac ganglia, which are abdominal nerve bundles that innervate the gastrointestinal tract.

A recent study conducted by researchers at Johns Hopkins University School of Medicine revealed similar data, but in mice. The Hopkins team also found that, when they injected an altered form of alpha-synuclein in the intestine of mice, it would first accumulate in the vagus nerve and subsequently spread throughout the brain.

With the findings from the new study, researchers now have more detailed evidence on how the disease most likely spreads.

This may put the scientific community one step closer toward developing more effective medical strategies to halt the disease, Borghammer said.

“For many years, we have known that Parkinson patients have extensive damage to the nervous system of the heart, and that the damage occurs early on. We’ve just never been able to understand why. The present study shows that the heart is damaged very fast, even though the pathology started in the intestine, and we can continue to build on this knowledge in our coming research,” he said.

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AV-101 Reduces Parkinson’s Dyskinesia Without Amantadine Side Effects, Preclinical Study Suggests

AV-101 results

VistaGen Therapeutics’ candidate, AV-101, reduced levodopa-induced dyskinesia (abnormal involuntary movements) while maintaining levodopa activity in a non-human primate model of Parkinson’s disease.

Importantly, AV-101 treatment did not cause the adverse side effects observed with amantadine, a therapy that works similar to AV-101 to ease Parkinson’s symptoms.

Hallmark motor symptoms of Parkinson’s disease include tremor, slowness of movement (bradykinesia), stiffness (rigidity), jerky movements (dyskinesia) and poor balance. As the disease progresses, patients typically need to gradually increase treatment dose for maximum benefit. Even after that, symptoms sometimes reappear or worsen due to the dopaminergic therapy’s gradual loss of efficiency.

Dyskinesia is one of the complications of long-term levodopa therapy that affects many patients with advancing Parkinson’s. These sudden, involuntary movements can be treated with amantadine, which acts on a specific part of NMDA receptors — molecular structures involved in neuronal communication — in the brain.

Amantadine’s exact mechanism of action is not fully understood, but studies indicate it inhibits NMDA receptors and reduces the levels of a chemical messenger called acetylcholine, which increases dopamine activity and provides anti-parkinsonian effects.

Nonetheless, the dose of amantadine needed to treat dyskinesia is often associated with side effects such as depression and cognitive impairment.

AV-101, developed by VistaGen, is an oral NMDA receptor antagonist that, unlike amantadine, acts on a different part of the receptor.

Researchers compared AV-101’s effectiveness to lower levodopa-induced dyskinesia to that of amantadine.

AV-101 was given to non-human primates that had been treated previously with MPTP, a neurotoxin that induces death of dopamine-producing neurons and mimics Parkinson’s symptoms.

AV-101 significantly reduced the abnormal, involuntary movements without affecting the timing, extent, or duration of the therapeutic benefits of levodopa.

“The antidyskinetic activity of AV-101 that we measured compares favorably with our observation with amantadine in parkinsonian monkeys,” Thérèse Di Paolo, PhD, one of the study’s authors, said in a press release.Di Paolo is on the faculty of pharmacy at Laval University in Quebec, Canada. Di Paolo is amongst the world’s leading researchers focused on Parkinson’s disease and levodopa-induced dyskinesia.

Importantly, the experimental therapy did not raise any safety concerns. “Better than amantadine, with its known side effects (in humans with Parkinson’s disease and in parkinsonian monkeys), we observed no adverse effects with AV-101,” Di Paolo said.

“We believe these preclinical data and AV-101’s positive safety profile in all clinical studies to date support AV-101’s potential to treat LID [levodopa-induced dyskinesia], while both maintaining the antiparkinsonian benefits of levodopa and without causing hallucinations or other serious side effects that may be associated with current amantadine-based therapy for LID,” noted H. Ralph Snodgrass, PhD, VistaGen’s chief scientific officer.

Scientists plan to present the preclinical results at an upcoming conference.

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Early Genetic Mutations May Contribute to Mitochondria Dysfunction and Parkinson’s Development, Study Suggests

mitochondria NESCs PD

Genetic mutations and consequent impaired activity of mitochondria — known as the powerhouses of the cell — may be a first step contributing to the development of Parkinson’s disease later in life, a new study suggests.

The study, “Neural Stem Cells of Parkinson’s Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality,” was published in Stem Cell Reports.

Parkinson’s disease is characterized by the degeneration and death of a specific group of nerve cells — called dopaminergic neurons —  in the midbrain, which are responsible for producing a neurotransmitter called dopamine. This neurotransmitter acts as a chemical messenger used by nerve cells to communicate.

It remains unclear what exactly triggers these damaging effects, but several studies have provided evidence that both genetic and environmental factors play a critical role.

Mitochondria are small organelles inside cells that provide energy and are known as the cell’s “powerhouses.” Parkinson’s patients are known to have impaired mitochondria activity, which is believed to contribute to the underlying mechanisms of the disease. Still, mitochondria’s role in Parkinson’s disease remains elusive.

An international team of researchers has now found that stem cells carrying a mutated LRRK2 gene —  previously linked to familial and sporadic Parkinson’s cases — recapitulate key mitochondrial defects described only in mature dopaminergic neurons.

The team analyzed 13 cultures of human-derived neuroepithelial stem cells (NESCs) — early progenitors of brain cells — that were obtained from three Parkinson’s patients carrying the mutated LRRK2 gene and four age- and gender-matched healthy donors.

They found that patient-derived NESCs had significantly altered patterns of mitochondrial gene expression compared with NESCs from healthy donors. Also, LRRK2 mutated stem cells had more mitochondria but these had aberrant structures and showed reduced capacity to produce energy. Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.

Overall, these findings indicate that mutated LRRK2 “interferes with mitochondrial dynamics, suggesting reduced mitochondrial quality,” the researchers wrote.

Further analysis confirmed that Parkinson’s patient-derived NESCs had increased production of toxic oxygen reactive species (ROS) — involved in oxidative stress — and had reduced survival compared with stem cells from healthy donors, which was consistent with impaired mitochondria activity.

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or ROS, are harmful to the cells and are associated with a number of diseases, including Parkinson’s disease.

In addition, patient-derived NESCs showed impaired ability to clear these damaged mitochondria, meaning that they were unable to restore the normal mitochondria balance and prevent their toxic effects.

“The detection of these (mitochondria features) in a developmentally early neural stem cell model” supports the hypothesis that “preceding mitochondrial developmental defects contribute to the manifestation of the (Parkinson’s disease) pathology later in life,” the researchers concluded.

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Inhibiting USP13 Enzyme Can Help Destroy Toxic Alpha-Synuclein Clumps, Mouse Study Finds

USP13 parkin alpha-synuclein

Inhibiting an enzyme called USP13 may represent an attractive therapeutic target for Parkinson’s and other neurodegenerative diseases, preclinical data suggests.

These findings also could hold important implications for a therapy currently being developed to treat Parkinson’s disease — nilotinib.

The study, “Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies,” was published in Human Molecular Genetics.

USP13 belongs to a large family of enzymes called de-ubiquitinases known for their ability to cut chains of a small protein known as ubiquitin that is present inside stress-induced clumps of proteins and other molecules.

Ubiquitination is like a cellular tagging system: By adding an ubiquitin molecule to a protein, it marks it for degradation.

Previous research has shown that USP13 and another similar enzyme called USP5 are important in helping to dismantle clumps of molecules that form when cells are stressed by external factors, called “stress granules.”

Now Georgetown University Medical Center researchers have found that one reason clumps of alpha-synuclein, known as Lewy bodies, develop and accumulate in the brain is that USP13 removes all the “tags” placed on alpha-synuclein that mark it for destruction, or ubiquitination. Toxic aggregates of alpha-synuclein accumulate and are not efficiently cleared.

Researchers analyzed brain tissue samples collected postmortem from 11 patients with Parkinson’s disease. USP13 levels were about 3.5 times higher than samples from subjects not affected by Parkinson’s.

To better understand the role of USP13, researchers used a genetic approach to either increase or decrease the levels of USP13 in mouse neurons cultured in a laboratory dish. These neurons expressed high levels of alpha-synuclein.

The presence of alpha-synuclein alone significantly increased the levels of parkin ubiquitination. Parkin is a protein often found mutated in some Parkinson’s patients.

The team had previously shown that an increase in parkin ubiquitination led to clearance of neurotoxic proteins, including alpha-synuclein, in several animal models of neurodegeneration.

However, expression of high levels of USP13 and alpha-synuclein together significantly reduced parkin ubiquitination, suggesting that USP13 can modulate parkin response.

“Taken together, these data suggest that USP13 may regulate parkin ubiquitination/de-ubiquination cycle,” the researchers wrote.

Additional experiments revealed that decreasing the levels of USP13 increased alpha-synuclein ubiquitination and destruction.

Knocking out the USP13 gene in a mouse model of Parkinson’s disease was able to prevent alpha-synuclein-induced death of dopamine-producing brain cells. Also, genetic inhibition of USP13 led to significant improvement in animals’ motor performance, while improving the clearance of alpa-synuclein toxic molecules.

Importantly, researchers found that a new therapy being studied to treat Parkinson’s disease, nilotinib, worked better when USP13 was inhibited.

Results from a recent Phase 2 clinical trial (NCT02954978) conducted by Novartis showed that nilotinib can modulate dopamine levels and metabolism, as well as prevent the formation of toxic alpha-synuclein aggregates.

Nilotinib is available under the brand name Tasigna as an approved treatment for certain types of leukemia.

“Our discovery clearly indicates that inhibition of USP13 is a strategic step to activate parkin … to increase toxic protein clearance,” Charbel Moussa, PhD, director of Georgetown University Medical Center Translational Neurotherapeutics Program and senior author of the study, said in a press release. “Our next step is to develop a small molecule inhibitor of USP13 to be used in combination with nilotinib in order to maximize protein clearance in Parkinson’s and other neurodegenerative diseases.”

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Investigational Herbal Therapy DA-9805 Shows Neuroprotective Effects in Parkinson’s Mouse Model

DA-9805 herbal treatment

An investigational herbal product called DA-9805 exerts its neuroprotective activity by preventing mitochondria damage in brain cells, a mouse study has found.

This compound is currently being evaluated in a Phase 2a clinical trial (NCT03189563) in early Parkinson’s disease patients.

The study, “Triple herbal extract DA-9805 exerts a neuroprotective effect via amelioration of mitochondrial damage in experimental models of Parkinson’s disease,” appeared in the journal Scientific Reports.

DA-9805 is an investigational compound being developed by the South Korean company Dong-A ST. It combines natural compounds extracted from three plants widely used in traditional Asian medicine: Moutan cortex, Angelica Dahurica root, and Bupleurum root.

Each of these plants is rich in compounds with broad therapeutic activities, including anti-inflammatory, antioxidant, anti-cancer, and analgesic proprieties.

Supported by their long history of use in traditional medicine for diseases caused by oxidative stress and inflammation, researchers hypothesized that they may also have the potential to treat Parkinson’s disease.

DA-9805 was obtained by extracting the main natural compounds of the three dried plants with 90% ethanol for 24 hours. A detailed analysis of the extracted compounds revealed the mixture was enriched for the active molecules paeonol, saikosaponin A, and imperatorin.

To evaluate the potential of the mixture, researchers exposed a cell line model often used to study Parkinson’s disease to increasing doses of DA-9805 or other reference compounds.

The treatment significantly prevented cell death induced by impaired activity of mitochondria — small cellular organelles that provide energy and are known as the “powerhouses” of cells — compared with the other tested compounds. The neuroprotective effect of DA-9805 was further confirmed when tested in cells collected from the superficial brain layer of rats.

Next, the team evaluated the effects of oral DA-9805 in a mouse model of Parkinson’s disease. This model was achieved by injecting animals with a neurotoxin called MPTP and its active metabolite MPP+, both of which exert neurotoxic effects on dopaminergic neurons — those that are mainly affected in Parkinson’s disease.

They found that treatment with DA-9805 effectively improved animals’ balance (bradykinesia) compared with placebo-treated mice. This positive effect on balance was similar to that observed in mice treated with approved Parkinson’s therapy Azilect (rasagiline).

Evaluation of dopamine levels in the striatum — the brain area most affected by the disease — showed that DA-9805, similar to Azilect, could also prevent dopamine reduction in the brain associated with Parkinson’s disease in these mice.

Importantly, although both compounds protected striatum dopaminergic neurons from death upon exposure to MPTP, DA-9805 showed a greater neuroprotective effect than Azilect.

These findings “suggest that DA-9805 has neuroprotective effects” in mice with Parkinson’s disease, according to the researchers.

Additional experiments revealed that DA-9805’s therapeutic effects were mediated by enhanced protection of mitochondria and their function, while reducing the levels of damaging oxidative molecules, also known as reactive oxygen species (ROS).

Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or ROS, are harmful to the cells and are associated with a number of diseases, including Parkinson’s.

“Given that mitochondria are involved in the pathogenesis of neurodegenerative diseases, we propose that DA-9805 may be a suitable candidate for disease-modifying therapeutics against Parkinson’s disease,” the researchers wrote.

DA-9805 is now being evaluated in a Phase 2a trial in patients with early Parkinson’s disease at the HealthPartners Institute in Minnesota.

Currently recruiting participants, the randomized, double-blind study is expected to enroll about 60 patients between the ages of 30 and 79 who have had mild to moderate Parkinson’s for two years or less.

Participants will be randomly assigned to receive a daily 45 or 90 mg dose of DA-9805, or a placebo for 12 weeks. Researchers will evaluate the safety and tolerability of the treatment, as well as its ability to improve patients’ motor function.

The study is expected to be completed by March 2019.

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Nicotinamide Exacerbates Motor Symptoms of Parkinson’s Disease in Mice

Nicotinamide motor symptoms

A form of vitamin B3 can promote degeneration of nerve cells linked to Parkinson’s disease and exacerbate disease manifestations in mice, a study reveals.

Despite the benefits of the compound demonstrated in previous studies, these new contrasting findings suggest that its mechanism of action is complex and not specific for therapeutic effectiveness in Parkinson’s disease.

The study, “The Histone Deacetylase Inhibitor Nicotinamide Exacerbates Neurodegeneration in the Lactacystin Rat Model of Parkinson’s Disease” was published in the Journal of Neurochemistry.

Nicotinamide, also known as niacinamide or nicotinic amide, is a derivate of vitamin B3 found in various foods including beef, chicken, pork, fish, peanuts, and mushrooms, among others.

It is the precursor of an important metabolic compound called NAD+ that is essential for cells to produce the energy they need to function normally. Besides this, nicotinamide also is known to act as an inhibitor of enzymes called HDACs. These enzymes are responsible for regulating the genes that are available to produce active proteins and those that are silenced and inactive, through a process called epigenetics.

In Parkinson’s, both cellular energy production mechanisms and epigenetic processes are deregulated. Given that, nicotinamide could hold therapeutic potential for this disease by providing dual-protective activity.

A previous study has shown that treatment with nicotinamide could improve energy production by supporting the formation of new mitochondria — small cellular organelles that provide energy and are known as cells’ “powerhouses.” The study also showed that the treatment could prevent the loss of motor function in a fly model of Parkinson’s disease.

To further explore nicotinamide’s potential, researchers treated rats with induced Parkinson’s disease for 28 days. The disease was chemically induced by injection of lactacystin in one side of the substantia nigra — the brain area affected most by the disease — promoting the accumulation of altered and toxic proteins, mimicking what occurs in human disease.

Contrary to what researchers expected, nicotinamide treatment enhanced the death of brain cells and structural brain changes. Also, animals treated with a nicotinamide showed increased rate of motor decline and development of behavioral deficits compared to untreated animals.

Despite these negative effects, analysis of the genetic landscape of these animals’ brain tissue revealed that nicotinamide treatment increased the expression of several neuroprotective genes. However, this potentially positive effect failed to increase neuroprotection; rather, it exacerbated neurodegeneration. (Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

“These findings highlight the importance of inhibitor specificity” to achieve therapeutic effectiveness in Parkinson’s disease, researchers wrote.

In addition, the team believes these results demonstrate “the contrasting effects” of nicotinamide in cell survival in different animal models of the disease.

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Engineered Protein May Lead to New Parkinson’s Therapy, Preclinical Study Suggests

Nurr1 protein

A modified form of a protein called Nurr1 that is able to protect against nerve cell death and restore dopamine production in a preclinical setting may pave the way for a possible new Parkinson’s therapy, a study reports.

The study, “Lethal Factor Domain-Mediated Delivery of Nurr1 Transcription Factor Enhances Tyrosine Hydroxylase Activity and Protects from Neurotoxin-Induced Degeneration of Dopaminergic Cells,” was published in the journal Molecular Neurobiology.

The nuclear receptor-related 1 protein, or Nurr1, plays a role in the development and survival of dopamine-producing neurons in the brain, a cell population that progressively degenerates in Parkinson’s disease, leading to lower dopamine levels.

As a type of protein called a transcription factor, Nurr1 controls the production of other key proteins in these neurons, while also regulating apoptosis, or “programmed” cell death.

An age-dependent reduction in Nurr1 levels has been proposed as one of the causes behind the loss of dopamine-producing neurons in Parkinson’s patients. Preclinical work showed that elevated levels of this protein provide anti-inflammatory benefits and neuroprotection.

Gene therapy approaches to deliver Nurr1 into animals and administration of compounds designed to boost its effects have shown promising results, but the protein’s inability to enter cells and reach their nucleus has remained a limitation for the potential development of therapies.

But now researchers from Ruhr Universitat Bochum in Germany and the U.S. National Institute of Allergy and Infectious Diseases at the National Institutes of Health have found a way to modify Nurr1 with a nontoxic bacterial protein fragment, a similar mechanism by which Bacillus anthracis infiltrates animal cells and causes anthrax, to help it get where it needs to go. A protein known as SUMO was also used to increase Nurr1’s stability.

“The fragment of bacterial protein that we used does not trigger diseases; it merely contains the command to transport something into the cell,” Rolf Heuman, one of the study’s authors, said in a press release.

After it is taken up by the cell, the protein fragment is detached, and Nurr1 is then able to reach its target genes by using the cell’s own nuclear import machinery.

Using human dopamine-producing cells grown in the laboratory, researchers found that successful delivery of modified Nurr1 was associated with higher levels of an enzyme called tyrosine hydroxylase, the key enzyme in dopamine production.

The team also tested the effect of modified Nurr1 on the cultured cells treated with the neurotoxin 6-hydroxydopamine, which causes the dopamine-producing cells to die and is used as a model for Parkinson’s. Nurr1 was able to inhibit the neurotoxin-induced degeneration of cells.

“Nurr1 fusion protein may contribute to the development of a novel concept of protein-based therapy,” the researchers wrote in the study.

Current Parkinson’s medications are not able to restore dopamine-producing neurons or stop their degeneration. A different approach, deep brain stimulation, has been effective in easing motor symptoms, but still carries safety risks.

“We hope we can thus pave the way for new Parkinson’s therapy,” said Sebastian Neumann, the study’s senior author. “Many steps still remain to be taken in order to clarify if the modified protein specifically reaches the right cells in the brain and how it could be applied.”

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Nanobodies Could Prevent Alpha-Synuclein’s Toxic Effects in Parkinson’s, Rat Study Suggests

Nanobodies alpha-synuclein

Antibody fragments, known as nanobodies, may be an efficient strategy to reduce abnormal alpha-synuclein protein aggregates and preserve motor function in Parkinson’s disease and other neurodegenerative disorders, a rat study suggests.

The study, “Proteasome-targeted nanobodies alleviate pathology and functional decline in an α-synuclein-based Parkinson’s disease model,” was published in the journal npj Parkinson’s Disease.

Parkinson’s disease belongs to a class of neurodegenerative disorders called synucleinopathies, characterized by the accumulation of misfolded alpha-synuclein aggregates. These abnormal protein aggregates are toxic to brain cells, triggering several damaging processes that promote the impairment and death of cells.

Given the key role of alpha-synuclein in the development and progression of Parkinson’s disease, many efforts have been made to find ways to effectively prevent its toxicity.

A team led by researchers at Rush University Medical Center in Chicago have developed a new strategy to target alpha-synuclein using nanobodies, small fragments of antibodies that can target and bind to specific proteins, tagging them for destruction.

In a previous study, the team showed that two particular nanobodies, called VH14 (also known as NAC14) and NbSyn87, could affect alpha-synuclein’s ability to aggregate. In the current study, they explored these nanobodies’ potential to prevent the progression of Parkinson’s in rats.

The team used an adenovirus-based system to deliver each nanobody directly into the substantia nigra — an area of the brain highly affected in Parkinson’s — of rats with Parkinson’s disease. This treatment was selectively administered to one side of the brain, or hemisphere, but not the other. An adenovirus is an inactivated virus that is very stable and easy to produce and can act as a “shell” to transport molecules inside cells. They are widely used for gene therapy purposes.

Treating the rats with either VH14 or NbSyn87 led to a nearly twofold reduction of the relative amount of toxic protein aggregates, compared with rats treated with a placebo. Notably, the nanobodies did not promote excessive destruction of alpha-synuclein, allowing residual protein activity to be maintained and preventing total loss of function.

Further detailed analysis revealed that rats treated with VH14 had 49% increased innervation in the striatum, compared with placebo-treated animals, and a 38% increase, compared with NbSyn87-treated rats. The striatum is a brain region involved in motor and reward systems, which receives dopamine inputs from different sources.

In addition, VH14 showed greater potential to protect the nerve cells in the substantia nigra from damage, whereas NbSyn87 showed just modest neuroprotective potential.

Evaluation of dopamine levels in the striatum region failed to show significant improvements upon treatment with either nanobody. Still, when comparing the treated versus non-treated brain hemispheres, animals treated with VH14 had about three times higher levels of dopamine, compared with placebo-treated rats.

Despite the variable impact on dopamine output, researchers reported that animals treated with VH14 had significant improvements in motor function over placebo-treated rats, restoring their walking ability and balance. Treatment with NbSyn87 also appeared to have a positive impact on preserving the animals’ motor function, but at a slower rate than VH14.

According to the researchers, these results demonstrate the “therapeutic efficacy of vector-delivered intracellular nanobodies targeting alpha-synuclein misfolding and aggregation in synucleinopathies such as Parkinson’s disease.”

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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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Sustained release Exendin-4 Reduces Neurodegeneration in Parkinson’s Rat Model, Study Shows

PT302 exendin-4

A new long-lasting formulation of exendin-4, called PT302, reduced neurodegeneration in a rat model of Parkinson’s disease, according to new data from a preclinical study by Peptron.

The study, “Post-treatment with PT302, a long-acting Exendin-4 sustained release formulation, reduces dopaminergic neurodegeneration in a 6-Hydroxydopamine rat model of Parkinson’s disease,” was published in Scientific Reports.

Parkinson’s disease is a chronic and progressive neurodegenerative disorder, mainly caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control.

Exendin-4, a peptide that activates the glucagon-like peptide-1 (GLP-1) receptor, is a hormone originally discovered in the saliva of the Gila monster. Previous studies have already shown that pre-treatment with exendin-4 significantly reduced dopaminergic neurodegeneration.

These promising results led researchers to propose GLP-1 receptor agonists as a new treatment option for several neurodegenerative diseases, including Parkinson’s, Alzheimer’s, Huntington’s, traumatic brain injury, stroke, and peripheral neuropathy.

However, the use of exendin-4 to treat patients with Parkinson’s has been severely hampered by the medication’s short half-life.

As a result, investigators at Peptron developed a new sustained release formulation of exenatide (marketed as Byetta and Bydureon) — a synthetic version of exendin-4 — called PT302, that extends the medication’s lifetime in the body.

“We are proud to apply our decades of experience in developing sustained-release therapeutics to the great unmet medical need of millions of people around the world who suffer from Parkinson’s disease,” Ho-Il Choi, PhD, CEO and director of Peptron, said in a press release.

In this preclinical study, researchers tested the effectiveness of PT302 in a rat model of Parkinson’s disease. First, they observed that a single under-the-skin administration of PT302 was able to sustain the levels of exendin-4 in the plasma of adult rats for more than 20 days.

Then, to determine a clinically relevant dose within this range, rats received PT302 once every two weeks, either before or following a lesion performed on one side of the brain. Remarkably, pre- and post-treatment with PT302 successfully reduced methamphetamine-induced rotation, a measure of brain lesion severity, after lesioning.

Post-lesion treatment with PT302 significantly increased brain tyrosine hydroxylase immunoreactivity (TH-IR) — a readout of dopaminergic neurons’ activity — in the substantia nigra and striatum on the lesioned side of the brain. Moreover, researchers found a direct correlation between the levels of exendin-4 in the plasma and TH-IR in the lesioned substantia nigra and striatum.

These findings indicate that post-treatment with PT302 sustains the levels of exendin-4 for longer periods of time and reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson’s disease at a clinically relevant dose.

“The peer-review and publication of this data is an important step in confirming the ability of our novel SR-exenatide drug to cross the blood-brain barrier and deliver long-acting therapeutic effects of the neuroprotective peptide. We are looking forward to beginning our Phase 2 clinical trial in Parkinson’s disease and advancing a novel therapeutic that could fight neurodegeneration,” Choi said.

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