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Nourianz Now Available in US as Add-on to Carbidopa/Levodopa to Treat Parkinson’s Off Periods

Nourianz tablets

Kyowa Kirin’s Nourianz (istradefylline) tablets are now available in the United States as an add-on treatment for off periods in Parkinson’s disease patients on a carbidopa/levodopa regimen.

Off periods — when the effects of a medication wear off before a new dose can be taken — are characterized by the re-emergence of Parkinson’s motor symptoms and are typically more common as the disease progresses. Within five years of starting levodopa/carbidopa therapy, approximately 50% of patients may experience off periods.

“We are pleased to offer patients Nourianz, the first and only FDA-approved adenosine A2Areceptor antagonist treatment for ‘off’ time associated with [Parkinson’s],” Tom Stratford, president of Kyowa Kirin USA Holdings, said in a press release. “Nourianz administered with levodopa/carbidopa therapy can help reduce ‘off’ time and increase ‘on’ time without troublesome dyskinesia.”

Nourianz blocks a receptor, known as the adenosine A2A receptor, found at high levels in the basal ganglia, a region of the brain that controls movement. By blocking this receptor, Nourianz can alter the release of neurotransmitters — chemical substances produced in response to nerve signals that allow nerve cells to communicate — in the basal ganglia, regulating motor activity.

The U.S Food and Drug Administration (FDA) approved Nourianz in August based on the results of four randomized, placebo-controlled Phase 2 and 3 clinical trials (NCT00955526, NCT00455507, NCT01968031, and NCT00250393).

The trials assessed the safety and efficacy of two doses (20 mg and 40 mg) of Nourianz to reduce the mean total hours of awake time per day spent in the off state and also lessen motor symptoms.

A total of 1,143 Parkinson’s patients taking levodopa/carbidopa, levodopa/benserazide, or levodopa and any other dopa-decarboxylase inhibitor were recruited. Treatment with Nourianz significantly decreased daily off time, compared with patients on a placebo, and improved motor function.

The most common side effects of Nourianz included involuntary muscle movement (dyskinesia), dizziness, constipation, nausea, hallucinations, and insomnia.

“In my clinical practice, I see patients who experience the troublesome effects of Parkinson’s disease and ‘off’ episodes that interfere with activities of daily living,” said Peter A. LeWitt, MD, a professor of neurology at Wayne State University School of Medicine and director of the Parkinson’s Disease and Movement Disorders Program, Henry Ford Hospital.

“Nourianz represents an important milestone and provides U.S. patients and their caregivers with a nondopaminergic, once-a-day oral treatment option to significantly decrease the amount of ‘off’ time,” LeWitt added.

Nourianz has been marketed in Japan under the brand name Nouriast since May 2013.

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Neuroscientist Awarded $2.9M NIH Grant to Study and Possibly Prevent Side Effects of Levodopa

levodopa study

The National Institutes of Health has awarded a $2.9 million grant to a Feinstein Institutes for Medical Research scientist working to better understand and prevent dyskinesia, a common side effect of the levodopa used to manage motor symptoms of Parkinson’s disease.

The five-year award went to David Eidelberg, a neurologist and neuroscientist noted for his pioneering work into brain networks in states of disease.

Levodopa is widely given to Parkinson’s patients to help with stiffness and slowness of movement. Naturally found in the body, it’s the precursor of dopamine, a signaling molecule that is involved in nerve cell communication.

Often combined with other medications to reduce side effects like nausea, levodopa is carried on circulating blood to the brain. There it’s converted into dopamine, which activates dopamine receptors to improve the workings of movement control centers in the brain.

However, after about five years of daily use, most patients develop levodopa-induced dyskinesias (LID) — uncontrolled, involuntary movements that interfere with daily activities — shortly after each dose. This side effect can be disabling and problematic for long-term Parkinson’s management.

“Since levodopa is regularly used to help ease the effects of Parkinson’s disease, it is essential to understand the therapy’s full effects on the cerebral blood vessels as well as neurons,” Eidelberg, head of the Feinstein’s Center for Neurosciences in the Institute of Molecular Medicine, said in a press release. “With this research, we hope to slow down or stop the development of LID in Parkinson’s patients.”

His study is titled “Neurovascular Effects of Dopamine Replacement Therapy in Parkinson’s Disease.”

Eidelberg is internationally known for using functional brain networks as neurological disease biomarkers to aid in Parkinson’s diagnosis, disease progression monitoring, and treatment assessment. He and his team are believed to be the first to observe uncoupling of the neuronal and cerebrovascular responses to dopamine in Parkinson’s patients, a pronounced occurrence in drug-induced dyskinesias. They seek to understand the neurovascular issues that underlie these dyskinesias by charting changes over time.

“Dr. Eidelberg is a leader in Parkinson’s disease research,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes. “This further support of his work by NIH offers a new path to understand this syndrome.”

In related news, a clinical trial may soon test a potential oral treatment for levodopa-induced dyskinesia, IRLAB Therapeutics announced in a company release. It plans to open a Phase 2b/3 study in the first half of next year assessing the safety and effectiveness of its oral candidate, IRL790, in Parkinson’s patients with these dyskinesias.

A four-week Phase 1b safety and tolerability study (NCT03531060) in 15 Parkinson’s patients in Sweden reported good safety (no serious side effects) and early evidence of possible benefits (drops in scores measuring dyskinesia) in people taking IRL790 compared to those given a placebo.

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Accordion Pill Enables Higher Optimal Doses of Levodopa Than Sinemet, Data Show

Accordion Pill

Patients with Parkinson’s disease who were treated with Accordion Pill Carbidopa/Levodopa (AP-CD/LD) tolerated a higher dose of levodopa and experienced less variability in plasma levels of this standard therapy than those on Sinemet.

Those are the top-line results from a Phase 3 clinical trial and data from a pharmacological study.

The effectiveness of levodopa may wear off with chronic treatment, resulting in the reappearance of motor complications, known as “off” periods. As this is associated with levodopa’s limited absorption in the upper gastrointestinal tract, Intec Pharma developed AP-CD/LD, which includes a gastric retention and release system to enable both immediate and controlled release. This controlled release mode prolongs the discharge of the medication into the stomach to eight to 12 hours, which may improve absorption.

The double-blind ACCORDANCE study (NCT02605434) is comparing AP-CD/LD with Merck’s Sinemet, an immediate release formulation of CD/LD. A total of 320 patients with advanced Parkinson’s were included in the double-blind part of the study (65.6% men, average disease duration 8.7 years), with the final visit occurring last May.

All eligible participants were on a daily levodopa dose within 400 and 1,300 mg and experienced at least 2.5 hours of off periods. After study completion, the patients could join a 12-month open-label safety extension study of AP‑CD/LD.

After two periods of six weeks each to stabilize and optimize patients on Sinemet and then on AP-CD/LD, the patients were assigned randomly to either approach over 13 weeks, with a two-week follow-up.

Two AP-CD/LD doses were tested: 50 mg of carbidopa, with 400 or 500 mg of levodopa, two or three times daily. Similar to the baseline percentage of daily off time, the patients’ mean age did not differ significantly between the two groups: 62.8 years in the AP-CD/LD group and 64.9 years in patients receiving IR-CD/LD.

At the recent  International Congress of Parkinson’s and Movement Disorder Society (MDS 2019),  R. Michael Gendreau, MD, PhD, Intec’s chief medical officer, presented the scientific poster “Patients Experiencing Motor Fluctuations with Parkinson’s Disease: Participant Characteristics in the ACCORDANCE Phase 3 Efficacy and Safety Trial of Accordion Pill-Carbidopa/Levodopa.” The presentation showed that patients on AP-CD/LD tolerated higher daily doses of levodopa than those taking Sinemet.

Specifically, 86.2% of patients taking AP-CD/LD achieved an optimal levodopa dose of 1,200 mg or greater, compared to only 19.7% among those on Sinemet.

Previous results from ACCORDANCE showed that, compared with Sinemet, AP-CD/LD did not provide greater reduction in daily off periods, benefits in “on” time without troublesome dyskinesia (involuntary body movements), or improved motor function scores, as assessed with the  Unified Parkinson’s Disease Rating Scale.

In a press release, Gendreau said that this lack of significant benefits of AP-CD/LD may have been due to confounding effects from patients whose dose was increased to the maximum (50/500 mg).

An analysis of lower doses showed a greater difference in mean daily off time between AP-CD/LD and IR-CD/LD in participants who were not dose-limited during the Accordion Pill titration process.

“This suggests that for many participants, AP doses higher than those available in this study may have been necessary to achieve optimal efficacy,” said Gendreau.

Also at MDS 2019, Jeffrey A. Meckler, Intec’s vice chairman and CEO, presented the study, “Pharmacokinetics of Accordion Pill-Carbidopa/Levodopa Following Multiple Doses in Patients with Parkinson’s Disease.” That presentation showed a pharmacokinetic (PK) comparison of AP-CD/LD 50/500 mg three times per day and the immediate release form (37.5/150 mg) five times daily in 12 patients. (Of note, PK refers to how a compound is absorbed, distributed, metabolized and eliminated by the body.)

After treatment with the immediate release form on day 1, the patients were instructed to take AP-CD/LD until day 8, when they returned to the clinic in the off state and received AP-CD/LD three times over 10 hours.

In line with Phase 2 findings — which also showed reduced motor fluctuations — preliminary results showed that AP-CD/LD provided less variability in levodopa’s plasma levels. Overall, as variable plasma levodopa levels have been associated with motor complications, the findings “suggest that treatment with AP-CD/LD may reduce motor complications,” the team wrote. AP-CD/LD was well-tolerated and no serious adverse side effects were reported.

“We believe the data underscored the potential of AP-CD/LD in PD while highlighting its long-term safety data,” said Meckler. “We have initiated a formal process for partnering AP-CD/LD in PD and this enhanced exposure will be important as we seek to partner AP-CD/LD for continued late-stage clinical development and commercialization in [Parkinson’s] patients.”

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Dopamine-Resistant Tremors Caused by Abnormal Brain Activity, Study Finds

Tremors

Parkinson’s patients whose tremors respond poorly to dopaminergic medications are likely experiencing abnormal brain activity outside the brain’s dopaminergic system, a study finds.

The results, “Cerebral differences between dopamine-resistant and dopamine-responsive Parkinson’s tremor,” were published in the journal Brain.

The main cause of motor symptoms in Parkinson’s disease is a lack of dopamine — a key brain chemical — resulting from a loss of dopaminergic neurons in the substantia nigra, a brain area responsible for controlling voluntary muscle movements. For that reason, levodopa, a dopamine replacement therapy, is often recommended to ease Parkinson’s symptoms.

“However, while dopaminergic medication effectively treats bradykinesia [slowness of movement] and rigidity, the effect on resting tremor is unpredictable and varies greatly between patients,” the researchers said.

“This observation casts doubt on the idea that Parkinson’s tremor has a dopaminergic basis,” they said.

One alternative explanation for the variability in treatment response is that tremors have different underlying causes depending on the patient. In some people, tremors indeed are caused by disturbances in the brain’s dopaminergic system — and for that reason, those patients respond well to dopaminergic medications. In other individuals, however, the tremors have a different underlying cause that these therapies are not able to tackle.

Researchers from the Donders Institute for Brain, Cognition and Behaviour, in the Netherlands, now set out to determine whether resting tremors that are resistant to dopaminergic medications are linked to abnormal brain activity in non-dopaminergic brain regions, such as the cerebellum, a region responsible for body balance.

To test this hypothesis, they first carried out a levodopa challenge, in which they administered the medication to 83 people with Parkinson’s who regularly experienced resting tremors. Their aim was to evaluate the patients’ response to the therapy.

After dosing, they selected the 20 participants who had the best treatment responses — tremors reduced by 71% after therapy — and the 14 patients who had the worst treatment responses. Those participants had their tremors reduced only by 6% after therapy.

Then, in the new subgroup of 34 patients with the best and worst responses to treatment, they used a technique called combined electromyography with functional magnetic resonance imaging (EMG-fMRI). That technique evaluated the participants’ tremor-related brain activity in two different settings: immediately after treatment with a placebo, or immediately after being treated with levodopa/benserazide combination therapy, administered at a dose of 50 or 200 mg.

Results showed that individuals whose tremors failed to respond to therapy had higher tremor-related brain activity in non-dopaminergic brain regions, including the cerebellum.

Conversely, in patients who had the best responses to treatment, analyses showed most tremor-related brain activity happened in dopaminergic brain regions. These regions included the thalamus, which regulates consciousness, sleep, and alertness, and the secondary somatosensory cortex, a region involved in pain processing.

In addition, researchers found that, in both groups, levodopa prevented abnormal brain activity associated with tremors in the thalamus. However, this protective effect was much stronger in people who responded well to dopaminergic medications compared with those who responded poorly to treatment.

“These results suggest that dopamine-resistant tremor may be explained by increased cerebellar and reduced somatosensory influences onto the cerebellar thalamus, making this region less susceptible to the inhibitory effects of dopamine,” the investigators said.

“These findings may have therapeutic implications, suggesting that an alteration of cerebellar reactivity and/or tremor-related processing may improve the clinical dopamine response of tremor,” they added.

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Nourianz Approved in US as Add-on Therapy to Carbidopa/Levodopa to Treat Off Periods in Parkinson’s

Nourianz FDA approval

The U.S Food and Drug Administration (FDA) has approved Kyowa Kirin’s Nourianz (istradefylline) tablets as an add-on therapy to treat off periods in Parkinson’s disease patients on a carbidopa/levodopa regimen.

Off periods — when the effects of a medication wear off before a new dose can be taken — are characterized by the re-emergence of Parkinson’s motor symptoms and are typically more common as the disease progresses.

Nourianz blocks a receptor, known as the adenosine A2A receptor, found at high levels in the basal ganglia, a region of the brain that controls movement. By blocking this receptor, Nourianz can alter the release of neurotransmitters — chemical substances produced in response to nerve signals that allow nerve cells to communicate — in the basal ganglia, in this way modulating motor activity.

FDA approval comes after the agency first rejected the therapy in 2008 due to concerns about its efficacy and asking for more data. Nourianz has been sold in Japan since 2013 under the brand name Nouriast.

“[This] approval is the culmination of decades of perseverance in exploring the science and clinical effects of istradefylline and inhibition of adenosine A2A receptor signaling in people with Parkinson’s disease,” Jeffrey S. Humphrey, MD, chief development officer of Kyowa Kirin Pharmaceutical Development, said in a press release. “We are grateful for the FDA approval and for the many dedicated scientists and  patients whose participation in our research programs has resulted in a new treatment option for Parkinson’s disease.”

The decision was based on data from four 12-week, placebo-controlled Phase 2 and 3 clinical trials (NCT00955526, NCT00455507, NCT01968031, and NCT00250393) that assessed the safety and efficiency of two doses (20 mg and 40 mg) of Nourianz to reduce the mean total hours of awake time per day spent in the off state and also lessen motor symptoms.

These trials enrolled a total 1,143 participants who were being treated with levodopa/carbidopa, levodopa/benserazide, or levodopa and any other dopa-decarboxylase inhibitor. Treatment with Nourianz significantly decreased daily off time when compared with patients on a placebo.

However, in 2016, data from one of the Phase 3 trials (NCT01968031), which evaluated the efficacy of Nourianz administered orally as a 20 mg or 40 mg once-daily treatment for 12 weeks, revealed a trend toward a greater reduction in the daily off-time compared with placebo, but this difference did not reach statistical significance.

New data from an interim analysis (which included 476 patients) of a post-marketing surveillance study conducted in Japan and submitted in October 2018 revealed that Nourianz was effective in 61.3% of patients, as assessed by the physician’s global assessment. Motor function improved, as observed by a decrease of 33.7 (after treatment) to 30.3 (from the beginning of the study) in the Unified PD Rating Scale (UPDRS) Part III (motor assessment) scores.

This new analysis also showed that off time was reduced in 38.2% of patients, and off-time symptoms improved in 44.7% of patients. Additionally, motor dysfunction was lessened in 48.5% of patients.

The most common side effects of Nourianz included involuntary muscle movement (dyskinesia), detected in 1% of the patients on Nourianz, dizziness, constipation, nausea, hallucinations, and insomnia. The FDA has requested that patients prescribed Nourianz are monitored for dyskinesia.

“Parkinson’s disease is a debilitating condition that profoundly impacts patients’ lives,” Eric Bastings, the acting director of the Division of Neurology Products at the FDA’s Center for Drug Evaluation and Research, said in an FDA press release. “We are committed to helping make additional treatments for Parkinson’s disease available to patients.”

Kyowa Kirin also has another adenosine A2A receptor antagonist, KW-6356, which is now undergoing testing in Phase 2 trials for Parkinson’s disease.

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Parkinson’s Forum Offers Patients and Caregivers Place to Learn, Share, and Foster Community

patient-caregiver forums

Online forums have markedly altered how patients, caregivers, and healthcare professionals communicate and connect. Even when miles apart, individuals can establish supportive relationships, share experiences and information, and sometimes simply vent.

BioNews Services, a leading online health, science and research publication company, has been rolling out its own forums, including one for Parkinson’s disease (PD), a progressive neurodegenerative disorder that affects roughly 1 million U.S. residents, and more than 10 million people worldwide. Moderated by patients and caregivers — nearly all of them BioNews columnists — these forums complement the company’s news and information websites, such as Parkinson’s News Today.

It’s that synergy of science and personal experience that sets BioNews’ forums apart.

“Patient forums are certainly not a new concept, but BioNews has something unique to offer our communities,” said Chris Comish, BioNews’ founder and CEO. “No other company has the ability to deliver such relevant content to our readers and use that as a starting point for driving conversation and discourse. We’ve had some really touching conversations occur, and have seen patients, particularly those newly diagnosed, find sources of hope and inspiration. It’s touched everyone involved.”

The company has introduced nine forums since last January — Parkinson’s was launched last July —  with more launching by year’s end. Its plan is to have a forum, customized by moderators, for each of its 60-plus rare disease sites. Every forum requires registration and moderator approval, and offers features such as private messaging and keyword search.

BioNews is working to add multimedia to each forum, including podcasts, YouTube videos, and flash briefings.

Within each forum are categories, also known as subforums. In A Forum for Parkinson’s Disease Caregivers, for example, members can connect with other caregivers and learn news ways to overcome challenges and practice self-care, like those presented here. Other posts examine Parkinson’s caregiving and income loss, and how to speak to a loved one with this disease.

In the subforum Diagnosis Information and General Questions, people newly diagnosed along with their caregivers and friends can ask questions about the disease and find information, all while supporting each other. Discussion topics range from personal reactions to a diagnosis to reasons for a misdiagnosis, like those detailed in this posted article.

The Living with Parkinson’s Disease subforum is a place for those who understand the day-to-day challenges the disease poses, including difficulties with walking and speaking. It’s also a resource for information about living with a chronic illness. There are posts about disease progression, for instance, and books by those with Parkinson’s about their journey.

Members can use the Parkinson’s Disease Symptoms space for resources to help them understand and cope with how Parkinson’s uniquely affects them. Because symptoms vary from person to person, the subforum is particularly popular. Subjects include trouble rolling over in bed, difficulty swallowing waterimproving handwriting, and the effects of dyskinesia — those uncontrolled and involuntary muscle movements.

In Parkinson’s Disease Alternative Treatments, participants can ask questions and share information about alternative or experimental therapies they’ve tried or are curious about, with the proviso that many suggestions are not science based, and that effects can vary. There are posts about medical cannabis, for example, gluten-free diets and rosemary essential oil.

The subforum Parkinson’s Disease Medications is for sharing information and experiences related to therapies, including levodopa and Xadago (safinamide). The platform Parkinson’s Research News keeps members apprised of the latest study and treatment advances. Members can connect with researchers, healthcare professionals, and other patients. Posts range from a study about sex and Parkinson’s to the preclinical results on a molecule that might reduce toxic protein buildups in the brain and reverse motor symptoms.

In Parkinson’s Disease and Exercise, participants can learn about, and share the benefits and challenges of, exercising. Entries touch on specific forms of exercise like swimming, or being overwhelmed by the volume of exercise required. Members can use the Parkinson’s Disease Awareness and Advocacy subforum to learn how to educate others about Parkinson’s, and to discover current and future efforts to heighten disease awareness.

In all, Jean Mellano, who is the Parkinson’s forum co-moderator along with Ally MacGregor, said she and others have found that levity is often most effective in disease management.

“Laughter is the best medicine,” said Mellano, who was diagnosed in 2015. “Having a sense of humor about the absurdity of some PD symptoms can help with the healing process. If we can share our stories with others, it may lessen the embarrassment caused by our symptoms.”

To help generate conversation, forum moderators regularly post topics within subforums. Sometimes the topic is based on a new column or news article. Other times, it’s something about day-to-day life. Moderators also post about their own lives, for instance, sharing thoughts on movies they’ve seen or their vacation photos. Some forums also have groups, both public and private subforum offshoots.

The forums’ framework was mostly developed by Kevin Schaefer with help from the social media team at BioNews. Schaefer is the company’s community development manager and an SMA forum moderator. He’s excited about the forums, and their growth and future potential.

“It’s just really cool to see a community evolving in each of them,” said Schaefer, who has SMA type 2. “They are as much about fostering community as they are about providing information. We want to do everything we can to engage with our members.”

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Specific Dopamine-producing Neurons Crucial to Adaptive Movement, Early Study Finds

motor skills and Parkinson's

Dopaminergic neurons — nerve cells gradually lost to Parkinson’s progression — that contain an enzyme called aldehyde dehydrogenase 1A1 are essential for acquiring the motor skills needed for proper movement in given situations, a mouse study reports.

The research, “Distinct connectivity and functionality of aldehyde dehydrogenase 1A1-positive nigrostriatal dopaminergic neurons in motor learning,” was published in Cell Reports. The work was developed by the Intramural Research Program of the National Institute on Aging (IRP-NIA).

Parkinson’s disease severely affects dopaminergic neurons, those that produce dopamine, a neurotransmitter (cell-signaling molecule) that relays information between nerve cells and between the brain and the rest of the body.  These neurons are found in two specific brain regions involved in motor control: the striatum and the substantia nigra.

Nerve cells may or not contain aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that is involved in cellular detoxification. Parkinson’s seems to mostly damage ALDH1A1-positive dopaminergic neurons, suggesting the enzyme may be a key player in this neurodegenerative disorder.

Both ALDH1A1-positive and ALDH1A1-negative dopaminergic nerve cells contribute to voluntary motor behavior. But the degree to which ALDH1A1-positive neurons are crucial to acquiring motor skills remains to be understood.

Using a mouse model of Parkinson’s, scientists targeted  dopaminergic neurons positive for ALDH1A1, and produced a detailed connectivity map of these specific neuronal networks in the mouse brain.

ALDH1A1-positive neurons were found to be in constant communication with other brain structures there. Importantly, researchers found that those dopamine-producing neurons of the striatum and substantia nigra that received the greatest percentage of molecular information (input) were located in the caudate-putamen nuclei, a brain region involved in movement control.

Researchers then selectively removed ALDH1A1-positive neurons to mimic the degeneration pattern observed in late-stage Parkinson’s disease. The animals’ ability to show new motor skills — new ways of voluntary movement, like foot position for maintaining balance while walking on a moving surface — was assessed using the rotarod test. In this test, mice must learn to balance while walking on a constantly rotating rod much like a treadmill.

Mice without ALDH1A1-positive neurons displayed a distinctly poorer ability to learn new motor skills, and slower walking speeds compared to control animals.

“Compared with a modest reduction in high-speed walking, the ALDH1A1+ nDAN-ablated mice showed a more severe impairment in rotarod motor skill leaning,” the researchers wrote. “Unlike control animals … [these] mice essentially failed to improve their performance during the course of rotarod tests.” (nDANs are nigrostriatal dopaminergic neurons.)

These animals were then treated with dopamine replacement therapy, either levodopa or a dopamine receptor agonist, one hour before a new motor skills assessment. Dopamine replacement therapy is standard treatment for the motor symptoms associated with Parkinson’s.

Levodopa (L-DOPA) treatment allowed the animals without ALDH1A1-positive neurons to travel longer distances, and to walk more frequently at higher speeds during a session. But it failed to improve their ability to acquire new motor skills during repeated tests. Treatment with a dopamine receptor agonist was also ineffective.

“When the ALDH1A1+ nDANs were ablated after the mice had reached maximal performance, the ablation no longer affected the test results, supporting an essential function of ALDH1A1+ nDANs in the acquisition of skilled movements. These findings are in line with the theory that nigrostriatal dopamine serves as the key feedback cue for reinforcement learning,” the researchers wrote.

These results provide “a comprehensive whole-brain connectivity map,” they concluded, and reveal a key role of ALDH1A1-positive neurons in newly learned motor skills, suggesting that motor learning processes require these neurons to receive a multitude of information from other nerve cells and to supply dopamine with “dynamic precision.”

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Bacteria in Gut Can Promote Parkinson’s by Altering Brain’s Immune Reactions, Study Says

'gut-brain axis' in disease

Bacterial infections in the intestines may trigger Parkinson’s progression by altering the immune system and damaging dopaminergic neurons, according to an early study supporting a “gut-brain” connection in this disease.

The findings, “Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice,” were published as a letter in Nature. A letter is a short report of original research that is of interest to investigators in other fields.

Strong evidence suggests mutations in the PINK1 gene, which codes for an enzyme that protects mitochondria — the cell’s energy-producing powerhouse — during periods of cellular stress are linked to early onset hereditary Parkinson’s. When mutated, tangles of the PINK1 protein build inside mitochondria in brain cells and damage them.

“Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles,” the researchers noted.

PINK1 is thought to participate in the clearance of damaged mitochondria, but studies do not consistently support the protein’s exact role in the cellular cleaning process.

Although mutations in PINK1 in Parkinson’s patients are known to promote disease progression, mice without the PINK1 gene are generally healthy. In fact, the animals display little, if any, Parkinson’s-related motor symptoms, suggesting the neurodegenerative disorder may be triggered by factors other than the loss of this protein’s function.

Based on their previous work, scientists at the Université de Montréal hypothesized that infection with a specific type of bacteria — called Gram-negative bacteria — could activate the immune system and “order it” to produce mitochondria-specific autoreactive CD8+ T-cells. Often called cytotoxic T-lymphocytes, CD8+ T-cells are very important for immune defense against intracellular pathogens (infectious agents).

Scientists first tested their theory in a lab dish. They infected mouse cells with several bacteria, including Gram-positive and Gram-negative ones, and observed that only the Gram-negative bacteria induced the activation of an immune response, with the highest levels obtained when the intestinal bacteria Escherichia coli (EPEC) and Novosphingobium aromaticivorans were used.

To determine whether Citrobacter — a Gram-negative mouse intestinal pathogen that is used as a model of human EPEC infection — triggered an immune activation, researchers then infected wild-type (normal) mice and animals engineered to lack the PINK1 protein. The bacteria were administered directly into the animals’ stomach by a tube (oral gavage).

In mice lacking the PINK1 protein, intestinal infection with this Gram-negative bacteria was found to activate immune mechanisms necessary for CD8+ T-cells to travel to peripheral tissues and the brain, compromising cell function.

Neurons within the animals’ striatum — a brain center crucial for motor control that’s severely damaged in Parkinson’s — were significantly degenerated, and as such, these mice exhibited Parkinson’s-like symptoms, the research team reported. The animals’ motor difficulties, which included limited back leg activity and slower movement four months post-infection,  were treated with  levodopa.

Microorganisms in the gut are known to communicate with the central nervous system through nervous, endocrine, and immune signaling pathways. Notably, studies suggest that harmful proteins related to Parkinson’s may start in the gut and later spread to the brain.

“These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease,” the researchers concluded.

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Gene Therapy Used to Produce and Sustain Dopamine in Brains of Primate Model of Parkinson’s

gene therapy study

Direct delivery of two dopamine-synthesizing enzymes to the midbrain, using a safe and inactive form of an adenovirus, was able to reverse signs of motor difficulties in a primate model of Parkinson’s disease, a study reports.

Continuous dopamine production via a gene therapy approach may be a promising one-time treatment strategy for Parkinson’s patients, providing long-lasting improvement and lowering the chances of motor fluctuations and other side effects associated with oral dopaminergic medication, its researchers suggest.

The study, “Vector-mediated L-3,4-dihydroxyphenylalanine delivery reverses motor impairments in a primate model of Parkinson’s disease,” was published in the journal Brain.

Treatment with levodopa — a precursor molecule of dopamine — remains the leading standard treatment of Parkinson’s, easing effects caused by damaged or dead dopamine-producing brain cells, the main cause of this disease.

Such treatment effectively helps to manage Parkinson’s motor symptoms, but dopamine agonists often becomes less effective over time. This is believed to be due, at least in part, to lesser production of the enzymes involved in dopamine production.

Recently researchers have focused on developing types of gene therapy that might overcome the long-term ineffectiveness of available treatments.

An international team of researchers designed a gene therapy approach to re-establish the amount of available enzymes known as TH and GCH1 — both necessary for dopamine production — in the midbrain.

Using an engineered adeno-associated viral (AAV) vector to simultaneously deliver the DNA coding sequences of the two enzymes, researchers injected different doses of the gene therapy directly into the putamen — one of the brain areas mostly affected by the disease — of 29 rhesus monkeys. Four animals were left untreated as a control group.

The putamen is also the brain region where most dopamine-producing cells are located.

One group of animals, initially given the lowest dose, was given a second and higher dose six months after a first injection to simulate “a clinical scenario where patients entering early in the safety trial could be offered a therapeutic dose at the end of the trial.” All animals were analyzed 10 months after the initial dosing.

“The re-dosed animals showed a significant recovery over the following 2 months, reaching the same level of recovery as the initial high-dose treatment group,” the study notes.

Importantly, the primates had been treated with increasing L-DOPA doses before the injection of the gene therapy, “given twice daily for 2 weeks to induce L-DOPA-induced dyskinesia,” the scientists wrote.

Findings showed that the therapy induced a significant and dose-dependent improvement in motor control up to a level similar to that obtained with the optimal dose of injectable levodopa.

Reported improvements in motor function also came without any signs of dyskinesia — the uncontrolled, involuntary movements that are often associated with long-term levodopa use.

Analysis of brain tissue samples collected from the monkeys showed that this AAV-mediated gene therapy could induce an increase of 760- to 5600-fold of TH and 1.2- to 1.5-fold of GCH1 enzymes compared to untreated animals.

“These results provide proof-of-principle for continuous vector-mediated L-DOPA [dopamine] synthesis as a novel therapeutic strategy for Parkinson’s disease,” the researchers wrote.

“This gene therapy approach may thus offer the possibility to prolong and sustain the ‘good years’ many patients with Parkinson’s disease experience during the initial stages of L-DOPA therapy,” they added.

The post Gene Therapy Used to Produce and Sustain Dopamine in Brains of Primate Model of Parkinson’s appeared first on Parkinson’s News Today.

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.

The post AV-101 Reduces Parkinson’s Dyskinesia Without Amantadine Side Effects, Preclinical Study Suggests appeared first on Parkinson’s News Today.