Lowering Iron Levels in Brain May Help Treat Parkinson’s, Trial in People with PKAN Says

deferiprone study

Binding to, or chelating, toxic levels of iron in the brain can slow the progression of a neurodegenerative disorder known as pantothenate kinase-associated neurodegeneration (PKAN), results from a Phase 3 trial show.

These findings may be relevant for other neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s and multiple sclerosis, which are also associated with high levels of iron in the brain, its researchers say.

The results, ”Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study,” were published in the journal The Lancet Neurology.

Iron is required for normal physiological functions; however, excessive levels can be toxic and abnormal high levels of iron are seen in several neurodegenerative diseases, from PKAN to Parkinson’s, Alzheimer’s, and MS.

Researchers conducted a Phase 3 trial (NCT01741532), called TIRCON, to evaluate the safety and efficacy of deferiprone in treating PKAN, a form of neurodegeneration that results in severe, involuntary muscle contractions (dystonia).

Deferiprone is an oral iron chelator approved to treat conditions linked with iron overload after blood transfusions in people with thalassemia, an inherited blood disorder characterized by lower levels of hemoglobin and fewer red blood cells.

The trial enrolled 88 patients with pantothenate kinase-associated neurodegeneration from four hospitals in Germany, Italy, England and the US. The participants, ages 4 and older, were randomized to deferiprone at 30 mg/kg a day (divided into two equal doses) or a placebo. Treatment was maintained for 18 months followed by an 18-month open-label extension phase, the TIRCON-Extension trial (NCT02174848).

Using magnetic resonance imaging (MRI) scans of the brain, researchers observed that treatment with deferiprone significantly lowered concentrations of iron in a specific part of the brain, called the globus pallidus, after 18 months compared to levels in the placebo group.

The globus pallidus is a region that is connect to several brain regions, and supports functions that include motivation, cognition and action.

These findings are in line with a previous Phase2/3 (NCT00943748) clinical trial’s results in Parkinson’s patients treated with deferiprone.

Treatment with deferiprone also decreased the number of PKAN patients who required other medications to control dystonia (11% compared to 21% in the placebo group). Slight, but not significant, improvements in disease progression with deferiprone treatment after 18 months were also seen compared to placebo. This was assessed using the Barry-Albright Dystonia (BAD) scale, which tests the severity of dystonia in eight different body regions.

This improvement appeared to be greater in a subset of later-onset patients with atypical pantothenate kinase-associated neurodegeneration, who had almost a 50% slower disease progression rate when treated with deferiprone compared to placebo. In placebo group patients who switched to deferiprone treatment in the TIRCON-extension trial, disease progression slowed by more than 60%.

Deferiprone appeared to be well-tolerated, with placebo and treatment groups reporting similar side effects. Anemia was the exception, as 21% of deferiprone treated patients reporting this side effect compared to no patients in the placebo group.

“The finding that brain iron can be markedly lowered by a chelator may have important implications also for age-associated neurodegenerative conditions such as Parkinson’s disease,” Thomas Klopstock, the Ludwig-Maximilians-University of Munich and the study’s first author, said in a news release.

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‘On Chip’ Blood-Brain Barrier Model Paves Way for Personalized Therapy, Study Suggests

BBB-chip Emulate

Using stem cells, researchers have recreated the complexity of the blood-brain barrier (BBB) — a critical protective brain structure — in a chip roughly the size of an AA battery.

This personalized BBB experimental model, which combines stem cell research with Emulate’s Organ-Chip technology, will allow scientists to better understand how the barrier works while also providing a novel way to investigate several human neurological diseases. By recreating true-to-life biology in a chip, researchers at  Cedars-Sinai can assess tailored strategies for people affected by progressive brain disorders, such as Parkinson’s disease.

The model was described in the study, “Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications,” published in the journal Cell Stem Cell.

The BBB is a semipermeable membrane, made of a complex network of blood vessels, that works as a natural filter that selects what reaches the brain. It blocks toxins and other foreign substances that are in the bloodstream from entering brain tissue, and potentially damaging it.

However, the BBB also can prevent “good” chemical agents from entering and targeting the brain, creating a major barrier for the efficient delivery of therapeutics that need to reach the brain and central nervous system to work.

Given the BBB’s complexities, transposing it represents an important step for the development and efficacy of therapies targeting neurological disorders, such as Parkinson’s and Huntington’s disease.

Indeed, some studies have suggested that several human neurodegenerative diseases, including Parkinson’s, are linked to defects in the BBB that may prevent healthy and necessary natural molecules from reaching the brain. That, in turn, supports the progression of the disease, this research suggests.

To date, it remains very difficult to study and fully understand how the BBB works, and to address the extent of its involvement in neurological diseases.

Cedars-Sinai researchers developed an “on chip” model of the BBB that specifically mimics the behavior of the barrier’s blood vessels and their interaction with brain cells.

The team used inducible pluripotent stem cells (iPSCs) derived from three healthy donors and one patient with Huntington’s disease to test their new experimental model. iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of any type of human cell needed for therapeutic purposes.

Using specific chemical stimulus, the researchers were able to transform iPSCs into mature BBB blood vessel cells or brain cells. The cells were then cultured on Emulate’s chip slide, which allowed a platform for cells to reconstitute the complex microenvironment of the brain and BBB.

The recreated BBB model was able to selectively allow the transport of some molecules from the BBB side across to the brain cells, confirming that it was working as as it naturally does in the body.

The model formed a functioning unit of a blood-brain barrier that mimicked what occurs in the body — including blocking the entry of certain drugs.

Researchers then created a model derived from cells from Huntington’s patients and people with Allan-Herndon-Dudley syndrome, a rare congenital neurological disorder. That barrier showed a different permeability pattern compared with the BBB model derived from healthy volunteers.

“Altogether, these results suggest that patient-specific iPSC-based BBB-Chips may be used to predict inter-patient variability in BBB functions,” the researcher said. They said the models also may help “predict human central nervous system drug penetrability.”

This BBB-chip model paves the way for a promising avenue for precision medicine, the investigators said.

“The possibility of using a patient-specific, multicellular model of a blood-brain barrier on a chip represents a new standard for developing predictive, personalized medicine,” Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, and the study’s senior author, said in a press release.

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Man-made DNA Molecules May Help Prevent Parkinson’s, Study Finds

man made DNA molecules

Osaka University scientists have built short fragments of DNA that can stop the production of abnormal alpha-synuclein protein in the brain — which may advance the development of new therapies for the control and prevention of Parkinson’s disease.

The study, “Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease,” was published in Scientific Reports.

“Although there are drugs that treat the symptoms associated with PD [Parkinson’s disease], there is no fundamental treatment to control the onset and progression of the disease,” Takuya Uehara, PhD, the study’s lead author, said in a press release.

It is believed that gene therapy could someday be used to treat or halt Parkinson’s. Potential therapeutic targets include genes associated with the disorder, such as the SNCA gene — the gene that codes for the alpha-synuclein protein. Mutations in SNCA lead to the production and accumulation of an abnormal, and harmful, form of the alpha-synuclein protein within brain cells of people with Parkinson’s. As the disease progresses, neuronal toxic protein buildup increases, eventually leading to cellular death. That, in turn, leads to the onset of disease-related motor and non-motor symptoms.

“The antisense oligonucleotide (ASO) is a potential gene therapy for targeting the SNCA gene. ASO-based therapies have already been approved for neuromuscular diseases including spinal muscular atrophy (SMA) [Spinraza] and Duchenne muscular dystrophy [Exondys 51],” the researchers said.

Japanese researchers now looked for ways to prevent the production of toxic alpha-synuclein, hoping to eliminate Parkinson’s molecular trigger. To do so, they designed 50 small fragments of DNA that mirrored parts of  the coding sequence of the SNCA gene messenger RNA (mRNA).

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced: DNA is first transformed into mRNA, and eventually, into a protein.

The man-made DNA fragments, also known as amido-bridged nucleic acid-modified antisense oligonucleotides (AmNA-ASO), were stabilized with resilient cyclic amide structures (hence the term “amido-bridged”). Amide are compounds that confer structural rigidity.

In total, these 50 molecules covered around 80.7% of SNCA’s mRNA. In doing so, engineered molecules were able to bind to their matching natural mRNA sequence, disabling it from being translated into a protein.

Using human embryonic kidney cells that naturally produce alpha-synuclein, scientists observed that several of these engineered molecules reduced SNCA mRNA levels. One of the constructs, specifically number 19, significantly decreased SNCA mRNA levels to 24.5% of the normal alpha-synuclein levels, “suggesting that AmNA-ASO [number] 19 is highly potent for targeting SNCA mRNA in human cultured cells,” the researchers said.

Importantly, this particular ASO was efficiently delivered into the brains of mice using an intracerebroventricular (a fluid-filled interconnected brain cavity) injection, without the aid of additional chemical carriers. The ASO was then mainly taken up by neurons and neuronal support cells.

Further testing, using a Parkinson’s mouse model that had disease-characteristic motor impairment, revealed AmNA-ASO number 19 successfully reduced alpha-synuclein protein levels, and significantly eased symptom severity 27 days after administration.

The researchers concluded that reducing alpha-synuclein mRNA and corresponding protein levels via gene therapy seems to enhance Parkinson’s-related motor manifestations in mice. This highlighted AmNA-ASO’s potential as a novel therapy for this neurodegenerative disorder.

The ASO Spinraza (nusinersen) was approved by the U.S. Food and Drug Administration (FDA) in December 2016 for treating spinal muscular atrophy. The FDA granted accelerated approval to Exondys 51 (eteplirsen) in September 2016, making it the first drug approved to treat Duchenne muscular dystrophy.

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At $52B Per Year, Economic Burden of Parkinson’s in U.S. Double Previous Estimates, Study Reports

economic burden Parkinson's

The annual economic burden of Parkinson’s disease on U.S. patients, families, and the federal government is nearly $52 billion, more than double the previous estimates, according to a comprehensive study by the Michael J. Fox Foundation (MJFF).

This is the first study to examine the various ways Parkinson’s affects a patient’s finances and their ability to participate in the labor market, according to a press release. The report is touted as the most complete assessment to date of the disease’s economic toll.

The $51.9 billion includes some $25.4 billion that goes toward hospitalizations, medications, and other direct medical costs, and $26.5 billion in non-medical costs such as missed work, lost wages, early forced retirement, and family caregiver time.

Previously, the combined direct and indirect costs of Parkinson’s in the United States were estimated at $25 billion annually. For many years, according to the release, the disorder’s financial impact was vastly underestimated.

Called “The Economic Burden of Parkinson’s Disease,” the study was conducted with support from the Parkinson’s Foundation, American Parkinson Disease Association, The Parkinson Alliance, and several pharmaceutical companies.

“There are a lot of surprise costs when you have Parkinson’s,” said Steve DeWitte, a Parkinson’s research funding advocate. “Beyond the rising costs of medications and healthcare, my family has shouldered the financial burden of my having to leave the workforce 15 years earlier than I had planned. That means our income dropped by more than half, and we’ve had to figure out how to stretch our budget to cover the everyday household tasks I can no longer physically do.”

The study also found that the federal government spends nearly $25 billion each year on patient care. Of that, $2 billion is paid through social security, with the balance handled by Medicare. Roughly 90% of Parkinson’s patients receives Medicare benefits.

“This data will help facilitate a new level of outcome-driven conversations with members of Congress who oversee federal programs that affect the lives of the 1 million people with Parkinson’s in the United States,” said Todd Sherer, PhD, MJFF’s CEO. “Investing more in research toward better treatments and a cure will ultimately relieve the burden on already-strained programs like Medicare, Medicaid and Social Security.”

These findings underscore the prospective impact of policy or treatment interventions, he added. Advocates now have more specific data they can use to educate lawmakers and to urge them to prioritize biomedical research investment and to develop support initiatives.

To understand and examine the cost components of Parkinson’s disease, the researchers used data from Medicare, the Centers for Disease Control and Prevention, the U.S. Census Bureau, and other sources. Such data-driven knowledge is expected to go a long way toward raising funds for research to find therapies to ultimately ease the growing burden.

“These results provide deep insight into the indirect costs — those costs the people living with Parkinson’s and their families must shoulder alone,” said James Beck, PhD, the Parkinson’s Foundation’s senior vice president and chief scientific officer. “Knowing this information will allow us to better serve people with Parkinson’s and their families in the areas they’re most concerned about and where we can have the most impact.”

The MJFF is now examining how this study can help shape its research policy priorities, as well as future public policy efforts related to the economic burden of Parkinson’s. For one, it plans to develop a project model to assess how specific actions — such as a ban on chemicals associated with Parkinson’s or federal approval of a disease-modifying treatment — would affect the economic burden.

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Midbrain Area Measurements Can Be Used to Distinguish Parkinson’s From PSP, Study Says

Midbrain area measurements

Midbrain area measurements can be used to distinguish patients with Parkinson’s disease from those with progressive supranuclear palsy, a study finds.

The study, “Midbrain area for differentiating Parkinson’s disease from progressive supranuclear palsy,” was published in Clinical Neurology and Neurosurgery.

Progressive supranuclear palsy (PSP), the second most common Parkinsonian syndrome after Parkinson’s disease, is characterized by gait, balance, speech, vision, behavioral, and cognitive impairments. Despite recent advancements in brain imaging techniques, distinguishing people with Parkinson’s from those with PSP at the earliest stages of the disorders is still challenging for clinicians.

To learn more, researchers from the Iran University of Medical Sciences and the Tehran University of Medical Sciences set out to assess whether midbrain area measurements could be used to differential people with Parkinson’s from those with PSP. The midbrain is the region connecting the spinal cord to the brain, and plays key functions in motor movement, and in auditory and visual processing.

The team used a technique called transcranial sonography (TCS) — a non-invasive, fast, and inexpensive procedure used to visualize brain structures in people unable to undergo magnetic resonance imaging (MRI).

The study enrolled a total 35 patients, 18 of whom had been diagnosed with Parkinson’s, and 17 with PSP. Participants had an average age of 67.2 years, and had been living with their disorder for approximately five years before enrolling in the study.

The results showed that patients with Parkinson’s tended to have larger midbrain areas compared with those with PSP (average of 4.86 cm2 vs. 3.61 cm2). The differences in midbrain size between those with Parkinson’s and PSP remained significant even after researchers normalized the midbrain area values to each patient’s disease duration.

Further analyses demonstrated that using the midbrain area as a diagnostic tool to identify people with Parkinson’s disease had higher sensitivity and specificity compared with other regions of the brain, such as the diameter of the third ventricle. Specifically, the sensitivity was 83.3% vs. 38.9%, while the specificity was 70.6% vs. 18.0%, respectively.

The third ventricle is one of the cavities in the center of the brain that is filled with cerebrospinal fluid (the liquid that circulates in the brain and spinal cord).

However, the diameter of the third brain ventricle showed higher sensitivity and specificity compared with the midbrain area in identifying PSP patients (sensitivity of 82.0% vs. 29.0%; specificity of 62.0% vs. 17.0%, respectively).

“Midbrain area in patients with PD was wider than those with PSP that was not affected by disease duration. In comparison with SN [substantia nigra] hyperechogenoicity [higher response during transcranial sonography ] and third ventricle size, midbrain area was the most accurate index for differentiating PD and PSP by [transcranial sonography],” the scientists said.

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MJFF Assists Nitrome Biosciences’ Pursuit of Parkinson’s Therapies

Nitrome Bioscience

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has awarded Nitrome Biosciences a Target Advancement grant to further the company’s development of therapies targeting Parkinson’s disease.

Specifically, the grant will be used to further Nitrome’s biological studies of a new Parkinson’s drug target.

The therapies are aimed at inhibiting a newly identified enzyme the company calls synuclein nitrase. The company said the enzyme causes or accelerates the nitration — a type of chemical modification caused by cellular stress — and aggregation of alpha-synuclein, a hallmark of Parkinson’s disease. At length, Nitrome will test whether an impeded enzyme can slow or stop Parkinson’s progression.

“We’re immensely grateful to MJFF for awarding this grant to Nitrome. This provides not only critically needed support but also shows interest in our unique approach to Parkinson’s disease drug development,” Irene Griswold-Prenner, PhD, said in a press release. Griswold-Prenner is Nitrome’s founder and CEO. “Additionally, the close connection with MJFF personnel provides important feedback as well as access to information, disease models and reagents.”

MJFF associate director of research programs, Luis M. Oliveira, PhD, calls the alpha-synuclein pathway a “compelling” target for development of Parkinson’s treatments.

“We are glad to support this study to mediate pathology and advance toward treatments that slow or stop disease progression,” he said.

Accumulation of alpha-synuclein, the chief component of Parkinson’s disease Lewy bodies, is found not only in the brain, but in the peripheral autonomic nervous system, which ultimately affects breathing and digestion.

A modified — nitrated — form of the protein can be found in salivary gland tissue of Parkinson’s patients. Because nitrated alpha-synuclein exists in early stages of PD, it could be a promising disease biomarker.

While starting with Parkinson’s, the company plans to use its discovery of the newly identified enzyme class to develop disease-modifying compounds for other neurodegenerative disorders, plus diabetes, heart disease and cancer.

The MJFF is the world’s largest nonprofit funder of Parkinson’s investigations. Its Target Advancement Program focuses on the identification of proteins and pathways involved in the onset and progression of the disease. Typically, such grants are for 12 to 18 months and are valued at up to $150,000. The amount of this grant was undisclosed.

“Highly nitrated and misfolded proteins play important roles in multiple neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis,” said Ephraim Heller, chairman of Nitrome’s board of directors. “Nitrome will deploy its platform technology to develop therapies for multiple diseases involving enzymatic protein nitration.”

According to the MJFF, nearly one million U.S. residents will be living with Parkinson’s by 2020. The disease affects 10 million individuals globally.

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Molecule May Halt Parkinson’s Progression, Study Using New Mouse Model Finds

anle138b molecule

A molecule called anle138b was able to reduce toxic alpha-synuclein aggregates, or clumps, in the brain — a key event linked to Parkinson’s — and reverse motor symptoms associated with the disease in a novel Parkinson’s mouse model.

The study, “Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model,” was published in Acta Neuropathologica. The work was funded by the charity Parkinson’s UK.

Many neurodegenerative disorders involve aggregation of misfolded (harmful) proteins in the brain. Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells, or neurons.

Anle138b has been shown to reduce toxic protein accumulation and delay disease progression in models of multiple system atrophy, Alzheimer’s disease and Parkinson’s.

Investigators from the University of Cambridge now evaluated the effects of anle138b in a new mouse model of Parkinson’s disease.

Although this molecule had previously been shown to reduce the clumping of proteins in other Parkinson’s models, the team wanted to understand its potential to treat the condition during its natural progression. To that end, they created a new mouse model that mimics the way alpha-synuclein gradually accumulates in specific areas of the brain, impairing neuronal communication and resulting in motor alterations.

The animals were nine months old before treatment initiation — around 46 human years. At the start of the treatment, the mice already showed low levels of dopamine in their striatum, a brain region involved in voluntary movement control that is severely affected in Parkinson’s. This reduction was associated with the onset of motor symptoms, including changes in gait that resembled some of the early motor symptoms seen in individuals with the disease.

However, the animals’ substantia nigra, another brain region involved in motor function that is also affected by the disease, had not yet been significantly damaged. Mice striatal (meaning “of the striatum”) and nigral (meaning “of the substantia nigra“) dopamine-producing neurons also exhibited alpha-synuclein aggregation.

Starting at nine months of age, mice were treated with anle138b for three months. Treatment reduced alpha-synuclein clumps, restored dopamine levels in the brain, and prevented dopaminergic nerve cell death. This was accompanied by gait improvements, suggesting that anle138b can effectively reverse, or at least halt, Parkinson’s progression.

These results indicated that “there is a window of time when it is possible to prevent [dopaminergic] neuronal death, even when striatal [dopaminergic] release is already impaired,” the researchers said. This means that if anle138b is given early on — before advanced nerve cell death — it may reduce  alpha-synuclein aggregates, potentially halting Parkinson’s progression.

“Our study demonstrates that by affecting early alpha-synuclein aggregation with the molecule anle138b in a novel transgenic mouse model, one can rescue the dopaminergic dysfunction and motor features that are typical of Parkinson’s,” Maria Grazia Spillantini, professor in the department of clinical neurosciences at the University of Cambridge, and the study’s lead researcher, said in a press release.

“The evidence from this early stage study builds on our understanding of how alpha-synuclein is involved in Parkinson’s and provides a new model that could unlock future treatments,” added Beckie Port, research manager at Parkinson’s UK.

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HYPE Protein Shows Promise in Treating Parkinson’s Disease, Research Shows

HYPE protein

The formation of alpha-synuclein aggregates in brain nerve cells (neurons) is thought to be one of the hallmarks of Parkinson disease. Researchers now have found that the activity of a single protein, called HYPE, may help halt alpha-synuclein accumulation and reduce its toxic outcomes, including neuronal death.

These findings, “Alpha-Synuclein Is a Target of Fic-Mediated Adenylylation/AMPylation: Possible Implications for Parkinson’s Disease,” were published recently in the Journal of Molecular Biology.

How Parkinson’s disease develops is still not well understood. However, evidence suggests that abnormal protein aggregates of alpha-synuclein, the main component of Parkinson’s disease hallmark Lewy bodies, are toxic and lead to neuronal death.

Clusters of misfolded (meaning altered structure) alpha-synuclein proteins also have been associated with disease severity. These aggregates lead to the formation of holes in the membranes of neurons, which affects their function and ability to communicate with other cells.

Previously, researchers had found that the HYPE protein can help cells cope with stress from misfolded proteins by promoting the addition of a chemical modification — called adenosine monophosphate (AMP), in a process known as AMPylation. They now asked whether HYPE also could play a role in Parkinson’s, specifically by modifying alpha-synuclein.

“Since HYPE plays such an important role in how cells deal with stress from misfolded proteins, we wondered whether diseases that result from protein misfolding were likely to need HYPE,” Seema Mattoo, PhD, an assistant professor of biological sciences at Purdue University and the study’s lead author, said in a press release.

“We know that in Parkinson’s disease, often the misfolded protein is [alpha-synuclein]. So we asked if HYPE could modify [alpha-synuclein], and if so, what are the consequences?,” Mattoo said.

Indeed, they found that HYPE is present in dopamine-producing neurons of the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in Parkinson’s disease – of rats.

Moreover, HYPE promoted the AMPylation of alpha-synuclein and this chemical modification decreased alpha-synuclein’s potential to aggregate.

When researchers looked at the protein under a microscope they found that HYPE changed its structure. While alpha-synuclein tends to twist, which may help promote aggregation, the new AMPylated protein did not twist as much, which may be why it aggregates less, Mattoo explained.

Importantly, AMPylation of alpha-synuclein also lessened the protein’s ability to make holes in neuronal membranes. “That means HYPE could possibly have a therapeutic effect on Parkinson’s disease,” Mattoo said.

Because alpha-synuclein is necessary for normal neuronal function, it has not been considered as a fit target for Parkinson’s therapy. However, these results open new possibilities.

“We’re all trying to apply a Band-Aid at the end of disease progression because we know aggregation causes the cells to become toxic, but how can we prevent that?” asked Mattoo. “There is still much to be understood mechanistically about it in the context of disease.”

Researchers now expect to expand their work to brain cells and animal models of Parkinson’s disease to validate their results.

“We’re in the early stages, but these results are giving us a new angle to look at potential therapeutics,” Mattoo said. “We’re trying to come up with drugs that could be used to manipulate HYPE’s activity. You could give them to patients who are starting to show signs of Parkinson’s or who are prone to having aggregated [alpha-synuclein]. That’s the direction we want to go.”

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Ultrasound Approach Eases Dopaminergic Brain Damage in Mouse Model of Parkinson’s


Using ultrasound coupled with the intravenous injection of microbubbles lessened brain damage in a mouse model of early Parkinson’s and may provide a noninvasive way to successfully deliver therapies into the brains of people with the disease, a study reports.

A clinical trial with Alzheimer’s disease patients has been approved by the U.S. Food and Drug and Administration to test the safety of the new device. Studies in people with Parkinson’s are expected to follow.

The study, “Amelioration of the nigrostriatal pathway facilitated by ultrasound-mediated neurotrophic delivery in early Parkinson’s disease,” appeared in the Journal of Controlled Release.

The inability to cross the blood-brain barrier – a thin membrane that separates the central nervous system (brain and spinal cord) from the circulatory blood system — has precluded the development of successful therapies for patients with neurodegenerative disorders such as Parkinson’s.

Aiming to improve treatment delivery into the brain, a team at Columbia Engineering used transcranial, focused ultrasound coupled with intravenously injected microbubbles containing neurotrophic factors (either through protein or gene delivery) to create a transient opening in the blood-brain barrier.

Neurotrophic factors are a family of molecules, mainly small proteins, that support the growth, survival, and differentiation of both developing and mature neurons. The neurotrophic factors used in the study were glial-derived neurotrophic factor and neurturin, both with beneficial effects in animal models of Parkinson’s.

The team had previously shown that focused ultrasound increased the delivery of neurturin to key Parkinson’s areas in the mouse brain.

They used a mouse model of early-stage Parkinson’s to test whether the combination approach eased damage in the brain’s nigrostriatal dopaminergic pathway — which includes the substantia nigra and the dorsal striatum and shows loss of dopamine-producing neurons during the early stages of Parkinson’s disease.

Unlike ultrasound or neurotrophic factors alone, the combination lessened damage by enabling the entry of these molecules into the brain. Specifically, the researchers found an increased number of nerve cells and nerve fibers, as well as greater levels of dopamine upon use of the combined treatment.

“Our findings provide evidence that the application of [focused ultrasound] at the early stages of [Parkinson’s] facilitates critical neurotrophic delivery that can curb the rapid progression of neurodegeneration while improving the neuronal function,” the scientists wrote.

“This is the first time that anyone has been able to restore a dopaminergic pathway with available drugs at the early stages of Parkinson’s,” Elisa Konofagou, the study’s senior author, said in a press release. “We expect our study will open new therapeutic avenues for the early treatment of central nervous system diseases.”

The new tool uses a neuronavigation system to direct the treatment in real time. “Neurosurgeons use such systems all the time to guide them for neurosurgery,” said Antonios Pouliopoulos, a scientist who worked on the development of the device. “Our group just replaced the surgical instrument with an ultrasound transducer to perform our non-invasive procedure.”

Unlike other groups currently pursuing more efficient treatment delivery into the brain, this device does not require nanoparticles nor magnetic resonance imaging (MRI). Compared with current helmet-shaped systems that use MRI, the new transducer is smaller, faster and about 10 times less expensive. And since it is portable, it may one day be used at home.

Konafagou recently won a four-year $2.5 million grant from the National Institutes of Health to explore a similar device for deep brain stimulation to discover how ultrasound activates nerve cells. She will also receive the 2019 Engineering in Medicine and Biology Society’s Technical Achievement Award for her work in ultrasound imaging and therapy.

“My grandmother has been suffering from dementia for more than five years,” Konofagou said, “so I know first-hand how essential it would be to have a simple device that can be wheeled into the patient’s home and offer a higher quality of life, especially for our rapidly aging population.”

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Davis Phinney Foundation for Parkinson’s Rides the Rockies Again

Ride the Rockies cycling tour

For 33 years, the Ride the Rockies cycling tour has lured thousands of cyclists and spectators globally to Colorado for 445 miles of strenuous biking that benefits area communities. This year, the June 9–15 tour will further its charitable impact by supporting organizations such as the Davis Phinney Foundation for Parkinson’s.

The charitable support is through the tour’s new Two Wheels for Change effort, which gives cyclists a chance to back nonprofit organizations that aim to make cycling accessible. Created by the Denver Post Community Foundation, the campaign also connects members of cycling communities.

Ride the Rockies organizers created crowdfunding pages for the roughly 2,000 participants in the tour. Team DPF, the Davis Phinney Foundation’s grassroots fundraising arm, will represent the Louisville, Colorado-based organization. Since 2012, the Ride the Rockies team has raised more than $625,000 for innovative Parkinson’s programs and patient advocacy and education.

”Last year was my first year as a participant,” Kevin Schmid, a Montana resident and Parkinson’s patient, said in a press release. “The whole week was amazing. We came together as a team. Everyone cheered each other on and pushed us through it.”

The riding adventure will feature the communities of Crested Butte, Gunnison, Buena Vista, Snowmass, Carbondale, Hotchkiss and Mt. Crested Butte. The top three fundraising teams will be eligible for prizes. There will be awards for individuals, too.

Each year, the event provides $5,000 community grants to local nonprofits, and generally spreads goodwill wherever the tour stops. The grant program funds nonprofit organizations that provide services for low-income youths through community programs that support recreation or youth education. To date, more than $585,000 has been granted to Colorado towns. Different communities are spotlighted annually.

The Davis Phinney Foundation was established in 2004 by Olympic cyclist Davis Phinney to Help Parkinson’s patients live well. In 2000, Phinney was diagnosed with young-onset Parkinson’s Disease. Team DPF supports the foundation through participation in a variety of athletic events, including those involving cycling.

In addition to the foundation, the other four organizations that will benefit are Adaptive Sports Center, Bicycle Colorado, Wish for Wheels and World Bicycle Relief.

Parkinson’s affects more than one million individuals in the United States.

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