From designer microbes to stem cells, researchers are investigating new strategies to treat bowel disease

June 12, 2018, University of Toronto

Gut organoids are three-dimensional balls of intestinal tissues grown in the lab from stem cells that allow researchers to examine the role different types of cells play in bowel health. The red stain marks cell outlines, while DNA is shown in blue 

The University of Toronto's David McMillen and his research team are creating a new life form to ward off disease – a bespoke, gut-dwelling microbe engineered to release drugs when needed.

"Our ideal outcome would be to be able to deliver a therapeutic into the gut with a programmable bacterium, which you could use for multiple diseases," says McMillen, an associate professor in the department of chemical and physical sciences at the University of Toronto Mississauga and leader of a Medicine by Design team looking to develop regenerative medicine therapies for intestinal diseases.

This new type of approach is one of several interdisciplinary projects funded by the regenerative medicine initiative with the aim of harnessing intestinal stem cells – cells that can self-renew and replace damaged cells in the gut – to boost the body's natural healing ability and perhaps even grow replacement tissue in a dish.

Other efforts are led by Jeffrey Wrana, a senior investigator at Sinai Health System's Lunenfeld-Tanenbaum Research Institute (LTRI) and a professor in U of T's department of molecular genetics, and Ulrich Tepass, a professor in the department of cell and systems biology, who are investigating how different cells contribute to gut development and maintenance.

The three team projects are among 19 from across U of T and its affiliated hospitals that Medicine by Design is funding to accelerate stem cell discoveries and translate them into new treatments. Medicine by Design is made possible thanks in part to a $114-million grant from the federal government's Canada First Research Excellence Fund – the largest single research award in U of T's history. 

Germs to the rescue

As many as 100 billion cells are thought to be shed every day from the intestine as part of wear and tear brought about by food digestion. The lost cells are quickly replaced, thanks to stem cells that dot the entire length of the intestine and are tasked with repairing tissue damage throughout life. But when this cell shedding and replacement process goes awry, it can lead to a host of diseases, from inflammatory bowel disease (IBD) to cancer.

If, for example, the cells of the intestinal lining are not replaced quickly enough, the gut can become "leaky" and unable to properly absorb food, clear waste and most importantly, prevent microbes from entering the body. This triggers inflammation, as seen in IBD, an umbrella term for Crohn's disease and ulcerative colitis, both of which negatively impact quality of life.

With one in 150 Canadians living with Crohn's or colitis, Canada has one of the highest incidences of IBD in the world, with economic costs estimated at $2.8 billion per year, according to the 2012 report by the Crohn's and Colitis Foundation of Canada. Among Canadian children under the age of five, the incidence of IBD is rising at an alarming rate, according to a study published last year.

While it is not clear what is behind the rise in IBD, it is thought that the microbiome – the gut's resident bacteria – could have something to do with it. Dubbed by experts as the "neglected organ," the microbiome is increasingly viewed as crucial for human health, especially for the proper development of the immune system.

It's fitting, then, that a Medicine by Design team is looking to fix the gut lining by means of an engineered gut microbe. Led by McMillen (pictured left), the team will insert genes into a bacterium that will allow it to sense and respond to inflammation in the gut in such a way that it can treat – and possibly even cure – IBD.

The project is rooted in the link between the microbiome and Crohn's disease, previously discovered by McMillen's collaborator Dana Philpott, a professor in the department of immunology. Philpott's team found that gut bacteria secrete a product called muramyl dipeptide (MDP), which binds to a receptor called NOD2 that resides inside the stem cells. A recent study showed that MDP acts via NOD2 to spur intestinal stem cells to proliferate and generate new cells for lining repair.

Current treatments include injections of steroids and other anti-inflammatory drugs that cause whole-body immunosuppression, which can be harmful. But these "band-aid sort of approaches" don't address the root of the problem and merely reduce the symptoms, says Philpott. By making a gut bacterium that can ramp up production of MDP during inflammation, "it should be possible to stimulate the human receptor to the right level and promote healing of the cells that are hardest hit during Crohn's disease," Philpott says.

To do this, the researchers will insert a synthetic genetic circuit inside a bacterium that will allow it to detect inflammatory molecules in the gut and use this as a trigger to release MDP for tissue repair.

Creating disease-fighting bacteria is at the cutting edge of synthetic biology, a field that strives to create cells with new and desired properties. "The main advantage bacteria have over drugs is that they can also sense disease," says McMillen.

Microbiome engineering is particularly appealing not only because bacterial genomes are small and fairly easy to tweak, but also because getting regulatory approval for any such therapy should be easier than for engineered human cells.

"Of all the things you could engineer, the microbiome is probably one of the safest places where you could start applying synthetic biology," says Keith Pardee, assistant professor at the Leslie Dan Faculty of Pharmacy, who is also on the team. "You're not modifying the patient, you are modifying the bacteria that will eventually wash out."

The team is taking advantage of the fact that gut microbes change their gene expression – and ultimately the molecules they release – in response to inflammation. Working with mice, their plan is to identify these molecules and turn them into universal inflammation sensors. As high-tech as it sounds, the daily grind of experiments is far from glamorous. It involves collecting mouse droppings to get the excreted bacteria, which are then mashed up and analyzed by DNA sequencing to find the genes that turn on in response to IBD.

This part of the project is being carried out in collaboration with John Parkinson, a senior scientist at the Hospital for Sick Children (SickKids) and a professor in U of T's department of molecular genetics, who is an expert in computational large-scale data analysis. Also on the team are Tae-Hee Kim, a scientist at SickKids and assistant professor in the department of molecular genetics, who is using a "gut on a chip" platform to study intestinal stem cells in more detail, and Radhakrishnan Mahadevan, a professor at U of T's department of chemical engineering and applied chemistry, who is engineering bacteria to produce high levels of the MDP molecule.

These images show the intestines of mice that have been given muramyl dipeptide (MDP) – left panel – and those that have not – right panel. The red stain marks cells that are proliferating, with more stain visible in the presence of MDP. A recent study showed that MDP acts via a receptor to spur intestinal stem cells to proliferate and generate new cells for lining repair. Credit: Sabrina Coquenlorge-Gallon/Tae-Hee Kim lab, SickKids

Another possible approach the team is investigating involves dampening inflammation locally and letting the intestine recover on its own. In this case, an engineered bacterium would release anti-inflammatory drugs only at the site of inflammation, which is beneficial in preventing all-body immunosuppression.

And unlike most cutting-edge medicines, the therapeutic bacteria need not cost a fortune.

"What we're making is self-replicating drugs that could treat patients essentially for free," says Pardee. "Everyone can grow a bug."

If all goes well, McMillen thinks that an IBD-sensing bacterium is within reach in three years' time.

"This is the most exciting project of my career," says McMillen. "Thanks to Medicine by Design, we have a shared goal among a group of researchers with a wide range of interests and this is catalyzing interactions and ideas we would not have had otherwise."

Towards organ replacement and repair

Using stem cells to grow replacement organs from scratch – or to boost the body's natural healing processes at will – are long-standing goals in regenerative medicine. But before these goals can be realized, researchers first need to get a clearer understanding of how different types of cells work together to drive organ growth and maintenance.

A few years ago, it became possible to grow three-dimensional balls of intestinal tissue from stem cells in a dish, also known as intestinal organoids or "mini-guts," which allow researchers to examine the diverse roles different types of cells play in bowel health and disease.

Wrana and his team are at the forefront of organoid research. With Medicine by Design funding, they are now developing new imaging technologies that, combined with genome editing and mathematical modelling, will reveal new insights into how individual cells contribute to intestinal repair.

"These discoveries can be applied to making the growth of human replacement tissues more efficient, or by illuminating how to get replacement tissue to functionally integrate into the recipient organ," Wrana says. "This research will also enable the design of therapies aimed at awakening dormant regenerative programs in damaged organs, thereby stimulating our own tissue to repair itself."

In addition to John Parkinson, team members include Laurence Pelletier and Daniel Durocher, both senior investigators at LTRI and professors in the department of molecular genetics; Daniel Schramek, an investigator at LTRI and an assistant professor in the department of molecular genomics; Sevan Hopyan, a senior scientist at SickKids and an associate professor in the department of surgery; Liliana Attisano, a professor in the department of biochemistry and in the Donnelly Centre for Cellular and Biomolecular Research; Christopher Yip, a professor at the Institute of Biomaterials & Biomedical Engineering (IBBME); and Luca Scardovi, an associate professor in the Edward S. Rogers Sr. Department of Electrical & Computer Engineering.

Getting the right size

Before researchers can grow replacement organs in the lab, they'll need a way to control their size. Organs that are too big or too small would be unsuitable for transplant, while any unchecked growth could potentially lead to cancer.

How organ size is controlled is what Tepass's team is trying to find out.

For the intestine, the key again lies in the lining, which harbours stem cells. It's now clear that cells that make up the lining do much more than just separate the intestine from other tissue. For example, as the intestine become distorted during food digestion, the cells in the lining sense and respond to mechanical forces by changing which genes are switched on. And when it comes to stem cells, stretching makes them proliferate more.

Being able to control this mechanism of cell proliferation could help regulate organ size in culture. "If the organ grows too fast, or becomes too big, you could use a drug that reduces mechano-sensitivity to slow down growth," says Tepass, adding that, while this research is still in early stages, one day such approaches could find a place in the clinic.

Tepass is searching for molecular players that link mechanical stress to changes in gene expression. But he is not looking for answers inside the gut. Instead, his team is studying the wings of fruit flies. The wing is composed of the same kind of epithelial cell sheet that forms the gut lining and envelops many internal organs. The study of fly wings helped researchers discover numerous genes that control organ size, which were subsequently also shown to have the same function in humans. Working with flies allows researchers to investigate complex cellular behaviour in the context of a whole animal, which cannot be readily replicated in cultured cells or organoids – and at a fraction of the cost and time it would take to do the same in larger animals such as mice.

"The process of going from stem cells to a functional organ is still largely a black box, something we don't know very well," Tepass says. "To control the overall size of the organ is a challenging biological question and we are using a simple organism to find key molecular players that orchestrate how big an organ gets."

Working with Helen McNeill, associate investigator at LTRI, and Anne-Claude Gingras, senior investigator at LTRI and professors in the department of molecular genetics, the team is identifying new genes and proteins that control growth. Also on the team is Jüri Reimand, principal investigator at the Ontario Institute for Cancer Research and an assistant professor in the department of medical biophysics, who is helping with large-scale computational data analysis. 

To see how these molecules are distributed in cells, Tepass has teamed up with Yip at IBBME and Rodrigo Fernandez-Gonzalez, an associate professor at IBBME and a member of the translational biology and engineering program at the Ted Rogers Centre for Heart Research, who are experts in combinatorial microscopy, live tissue imaging and quantitative image analysis.

Tepass emphasizes that "support from Medicine by Design has been essential to bringing together researchers from different fields to refocus their efforts on the question of controlling organ size. On a fundamental level, the understanding gained here is expected to guide rational approaches to organ regeneration and repair in the clinic."

Provided by: University of Toronto 

https://medicalxpress.com/news/2018-06-microbes-stem-cells-strategies-bowel.html

Bastyr University Researcher Will Lead Summer School Program for Parkinson’s Patients

JUNE 12, 2018 BY CAROLINA HENRIQUES 

Laurie Mischley, PhD, a researcher at the private, non-profit Bastyr University, is launching the first-ever summer school program for Parkinson’s disease patients.

This August, Mischley will facilitate two medical-educational retreats at Bastyr as part of the new “PD Summer School.”

Until June 15 those interested can apply to one of the five-day itineraries, including therapeutic strategies and tips designed to help individuals with Parkinson’s better navigate issues and concerns related to their disease.

The program is available in two sessions. One session will take place from Aug. 12-17 and another from Aug. 19-24. Both sessions will be held at the Kenmore Campus, in Washington state.

Fees for participating are $4,000 for patients and $500 for partners, excluding costs of accommodation for the week. Included in the registration fee are more than $2,000 worth of laboratory evaluations.

The entire cost of the program can be submitted to insurance companies for reimbursement, as they are equivalent to about 20 hours of patient care plus labs, depending on the insurer and insurance plan.

Topics covered during the sessions include strategies for disease modification, scientific causes behind Parkinson’s and laboratory evaluation of the disease, how to manage motor symptoms, environmental medicines, diet and exercise, among others. All sessions will be lectured by internationally-recognized top Parkinson’s experts.

The PD Summer School was designed using results from a 2014 study, which demonstrated that Alzheimer’s patients’ symptoms could be partially reversed using a comprehensive, personalized therapeutic program based on the underlying development of the disease. Mischley believes that a similar approach also can be applied to Parkinson’s.

“Using a similar approach for PD, people often report a reduction in medication and an improvement in symptoms. I don’t think neurodegenerative diseases are nearly as progressive as most people think they are. People just need to stop doing the things that are causing the degeneration,” she said in a press release.

“PD Summer School patients/students and their caregivers will go home with biologically plausible, real-world action items. The therapies we teach are evidence-based, supported by published, peer-reviewed literature,” Mischley added. “They’ll also have a lot of fun, enjoying delicious and nutritious foods, receiving massages and participating in meditation and exercise classes between lectures and appointments. Family members are invited to attend with their loved ones for a small fee so they can share the experience.”

Participants will be asked to complete personalized lab tests prior to attending the week-long program. Each attendee will then receive recommendations catered to their unique symptoms, context and priorities. These recommendations will be shared with their physicians back home for follow-up.

As well as facilitating the PD Summer School, Mischley is conducting the CAM Care in Parkinson’s Disease study — now recruiting (NCT02194816) — which aims to identify factors (including practices, beliefs, and therapies) associated with improved quality of life and fewer Parkinson’s symptoms.

Catered meals will be provided at no cost at Bastyr’s Dining Commons, with nutrition and cooking demonstrations in the Bastyr Nutrition Kitchen. Information about accommodation is available at:   https://www.bastyrpdschool.org/accommodations

https://parkinsonsnewstoday.com/2018/06/12/bastyr-university-will-host-summer-school-parkinsons-patients/?utm_source=PAR+E-mail+List&utm_campaign=12d9fd9eff-RSS_WEEKLY_EMAIL_CAMPAIGN_DAILY_US&utm_medium=email&utm_term=0_62dd4fb5e3-12d9fd9eff-71459285

Nuplazid’s Risks in Treating Parkinson’s Psychosis Don’t Appear Exceptionally High, Experts Say

June 11, 2018  GRACE FRANK

The controversy surrounding Nuplazid (pimavanserin), Acadia Pharmaceuticals‘ approved treatment for psychosis in Parkinson’s patients, has made its way to scientific journals. But experts appear to take a more questioning view of the medication’s risks than that aired by general media.

A clinical trial comparing the effectiveness and benefits of Nuplazid to other antipsychotics used to treat these patients would be warranted, and ideally pit the medication against clozapine, an editorial in The Lancet said. But the piece also noted that clozapine, a schizophrenia treatment, is not approved for Parkinson’s disease and is used off-label, complicating matters.

The editorial, “Difficult choices in treating Parkinson’s disease psychosis,” was published on May 29.

Focusing on the “relative risk of pimavanserin” in comparison to psychosis medications like clozapine and quetiapine, it also noted that “it is important to remember that safety concerns were expected and deaths can occur commonly in patients with Parkinson’s disease psychosis — a fact acknowledged by the FDA during its assessment — because these patients are frail, and are usually in the end stages of the disease.”

Still, the editorial recommended that a randomized clinical trial assessing Nuplazid’s risks and benefits in Parkinson’s patients be pursued, and research “continue into novel drugs for psychosis in frail populations.”

In the journal Neurology Today, meanwhile, three neurologists questioned reports of an unusual risk to Parkinson’s patients being treated with Nuplazid for psychosis.

“In my personal experience with pimavanserin, it is effective in a majority of PD [Parkinon’s] psychosis patients,” said Rajesh Pahwa, MD, a professor of neurology and chief of the Parkinson & Movement Disorders Division at the University of Kansas Medical Center in Kansas City. “We need to further study the reports of increased mortality, but in a scientific manner.”

The journal’s “Article in Brief,” published June 7, recounted the controversy concerning Nuplazid, the first medication approved by the U.S. Food and Drug Administration to treat Parkinson’s psychosis, or disease-related hallucinations and delusions, in 2016.

Nuplazid works differently from other anti-psychotic medications in that it does not block dopamine — a brain neurotransmitter crucial to movement and motivation, and the target of treatments for Parkinson’s movement difficulties — focusing instead on a subfamily of serotonin receptors (5 HT2A) of importance to cognition, memory, and the ability to learn.

The news channel CNN reported in April that the FDA’s Adverse Event Reporting System (FAERS) showed a total of 700 deaths, including 500 in Parkinson’s patients in which the medication was the only agent likely involved.

The FDA initially responded by noting that “FAERS data by themselves are not an indicator of the safety profile of the drug or biologic,” and emphasizing it had placed a “boxed warning” on Nuplazid highlighting its risks. A boxed warning is the strictest warning on product labeling that can be given an approved medication, but one — warning of an increased risk of mortality and morbidity in people with dementia — given on all antipsychotics, The Lancet commentary noted.

Later, the FDA acknowledged that is was continuing to keep close watch on Nuplazid and its use in Parkinson’s patients. The CNN report led to a 20 percent drop in Acadia’s stock in the days after its airing.

But, as Pahwa argued, the U.S. Medicare database show that mortality rates (per 100 patient years) are 7.3 for Parkinson’s patients without psychosis, and 28 for patients with psychosis — with a mortaility rate of 18.6 for those using quetiapine off-label, compared to 12.4 in post-marketing data for pimavanserin.

Joseph Jankovic, MD, director of the Parkinson’s Disease Center at Baylor College of Medicine in Houston, told Neurology Today that his patients largely have responded well to Nuplazid treatment.

“While not all patients are completely satisfied, many of my patients have experienced marked improvement in their visual hallucinations, paranoia, and other psychotic symptoms,” Jankovic said. “I suspect that the death rates in elderly patients with advanced PD and psychosis are higher than in a control population without these problems, so it’s not surprising to see deaths in such patients who are taking pimavanserin, but the cause-effect relationship has not been established.”

He preferred to recommend that physicians simply continue to closely monitor their patients.

A similar view was voiced by Cynthia Comella, MD, a professor of neurology at Rush University Medical Center’s Parkinson’s Disease and Movement Disorders Section in Chicago.

“I think it is too soon to be concerned specifically about this drug,” Comella said. “I feel that we need to be cautious with all of these drugs. I especially have concerns prescribing them in elderly patients because they are more fragile and usually have additional disorders and health conditions.”

According to the Neurology Today article, Pahwa has received consulting fees from about a dozen pharmaceuticals and government agencies including Acadia, but no research grants from Acadia. Jankovic and Comella reported no conflicts of interest.

https://parkinsonsnewstoday.com/2018/06/11/risk-nuplazid-treating-parkinsons-psychosis-not-exceptionally-high-experts-say/

Long Daytime Naps Linked to Higher Risk of Parkinson’s in Older Men in 11-year Study

JUNE 11, 2018 BY ALICE MELÃO 

Taking long daytime naps — rather than being excessively sleepy during day hours but not napping — appeared to be linked to a two-times higher risk of Parkinson’s disease in older men in a long-term study.

The study, “Excessive daytime sleepiness, objective napping and 11-year risk of Parkinson’s disease in older men,” was published in the International Journal of Epidemiology.

About half of all Parkinson’s patients report with some form of disturbed sleep and feeling disagreeably sleepy during waking hours. While this is a common non-motor symptom of the disease, it is still unclear if daytime sleepiness could be an early factor — or a risk factor — for Parkinson’s disease.

University of California researchers conducted an 11-year prospective study to understand the association between daytime excessive sleepiness and napping, and the risk of developing Parkinson’s.

They evaluated daytime sleeping patterns in 2,920 men, mean age 76.3 years, who did not have a history of Parkinson’s. Participants reported their sleeping routines and wore a small device on their wrist that objectively recorded their activity and napping habits.

Among the study group, 7.4% of participants reported excessive daytime sleepiness but taking naps for less than one hour during the day. Another 28.1% did not report excessive sleepiness but napped for more than one hour each day.

About 5% reported being both sleepy during daytime hours and taking spending considerable time napping — more one hour each day. These men were found to be older, overweight, showed depressive symptoms, lower cognitive function, and were more likely to have a medical history of stroke, coronary heart disease, hypertension, or diabetes.

The remaining men — 59.5% — reported neither excessive daytime sleepiness nor a habit of daily napping.

During the 11 years of follow-up, 106 of these men were diagnosed with Parkinson’s disease.

Men with excessive daytime sleepiness who also napped for more than one hour a day were 2.52 times more likely to develop Parkinson’s than those who neither took daytime naps or felt extremely sleepy during the day. Men who took long daily naps — but without expressing excessive daytime sleepiness — had a 1.96 increased risk of developing the disease. No link was found between daytime sleepiness alone and Parkinson’s, the study reported.

Rather, longer times spent napping each day, rather than excessive daytime sleepiness, were linked to a higher risk of developing Parkinson’s. “Men with a napping duration of at least 1 h per day were more than twice as likely to develop Parkinson’s compared with those who napped for less than 30 min per day,” the researchers wrote.

Although they lacked information on exactly when a participant developed Parkinson’s, their results suggest that “napping precedes PD diagnosis by at least 2 years,” the researchers wrote.

“Objective measures of napping might be a potentially useful early marker of future risk for Parkinson’s disease,” they added.

Additional studies are needed to further investigate the predictive value of long napping in addition to established risk predictors for the disease, the researchers said.

But they thought their results “might open up new avenues for the early detection of Parkinson’s in the elderly,”  and contributed to treatment strategies that may “be critical for better management of Parkinson’s disease in the long run,” they concluded.

https://parkinsonsnewstoday.com/2018/06/11/long-daytime-naps-linked-to-risk-of-parkinsons-disease-in-older-men/

Making People Laugh In Spite of Life’s Circumstances

JUNE 11, 2018  "SHERRI WOODBRIDGE"

Everywhere you turn these days there is so much negativity. It’s hard to wrap your head around the fact that there are some encouraging stories out there. These are stories of people who have fought fear while battling their diseases and are winning the battle. People who have taken their negative circumstances and responded in such a positive way that they’ve brought hope to others. People who have been the brunt of jokes because of their disabilities and who have become an inspiration for others.

One such man has become an inspiration to others around the globe. His name is Lee Ridley. Some readers may be familiar with him, as he was the latest winner of “Britain’s Got Talent.” The stand-up comedian is also known by his stage name, “The Lost Voice Guy.” What makes Lee unique in winning the final spot is that he has cerebral palsy, a congenital disorder of movement, muscle tone, or posture, and he is mute. Diagnosed as an infant, he uses Lightwriter, a speech-generating device that enables him to speak to his audience.

Lee has worked in several positions where he has been able to use his master’s degree in online journalism and his undergraduate degree in journalism.

While I watched the final show of “Britain’s Got Talent,” I was laughing out loud at his act, and when he won, I honestly don’t think I’ve ever seen such a winsome smile come across anyone’s face as the smile that came across Lee Ridley’s face at that moment.

As a young boy, it’s likely that he had to fight off smirks and scoffing, teasing and taunting, and then through the teen years he may have been the brunt of immature jesting and joking. He had to learn to buck up, tighten his bootstraps, and keep moving forward. The young man he has become has undeniably made a difference in his world and the world as a whole.

Where so many would have resorted to self-pity, he looked for a purpose. Where others might have felt consumed by darkness, he found light and moved toward it. He refused to give up, or give in, and he did it by taking his imperfections and using them to make the rest of the world laugh. And if laughter is indeed the best medicine, Lee Ridley is healing people everywhere, one joke at a time.

***

Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s Disease. 

https://parkinsonsnewstoday.com/2018/06/11/parkinsons-lee-ridley-making-people-laugh/

This 'light-activated' drug could treat Parkinson's

June 11, 2018    By Catharine Paddock PhD

For the very first time, scientists have developed a light-activated drug for treating Parkinson's disease directly in a targeted part of the brain.

A new light-activated drug could help to treat Parkinson's disease.

The drug — which is activated by shining light down an optical fiber implanted in the brain — reduced Parkinson's symptoms and improved motor function in mice.

In a paper about the work now published in the Journal of Controlled Release, the international team suggests that the "light-operated" drug could potentially treat other movement disorders.

When activated by light, the drug — called MRS7145 — blocks a protein called the "adenosine A2A receptor."

Previous studies have already suggested that the adenosine A2A receptor is a promising target for brain disorders such as Parkinson's disease.

However, as the authors explain in their paper, adenosine receptors are located throughout the brain, making it difficult to use them for selecting and targeting only specific parts of the brain.

By allowing "the spatiotemporal control of receptor function," the new light-activated drug overcomes "some of these limitations," note the authors.

Parkinson's and photopharmacology

In excess of 10 million of the world's population has Parkinson's disease, including 1 million people in the United States alone.

The disease is lifelong and gets worse with time. It mainly affects movement, producing tremors, stiffness, slowness, and problems with balance and coordination. Nonmovement symptoms can also arise, such as constipation, disturbed sleep, depression, anxiety, and fatigue.

Parkinson's disease does not usually strike before the age of 50; only around 10 percent of cases are diagnosed at an earlier age.

It arises due to death of nerve cells, or neurons, in a part of the brain called the substantia nigra. These neurons make a chemical messenger called dopamine, which, among other things, is important for controlling movement.

The goal of many drugs intended to treat Parkinson's disease is to restore dopamine levels in the brain. The blocking of adenosine receptors has been suggested as a target for such treatments, because it can raise dopamine levels.

Photopharmacology is a relatively new medical field that develops drugs whose power can only be switched on and off using light.

The approach offers the possibility of controlling the precise location of drug release in the body, thereby limiting any off-target side effects. An example is the precise targeting of chemotherapy drugs to specific cancer cells.

It also allows precise timing of the release of the drug. The release of type 2 diabetesdrugs that individuals can switch on and off as and when required is an example of this.

Precisely timed dosing is a distinct advantage in the use of drugs that gradually lose their efficacy and thus require bigger doses to work. This is what happens with levodopa, the most common drug for treating Parkinson's disease.

Light-activated drug tested in mice

MRS7145 is a light-sensitive derivate of "SCH442416, [which is] a selective antagonist of adenosine A2A receptor."

The compound is chemically inactive until it is irradiated with light of wavelength 405 nanometers, which is in the violet, visible part of the spectrum and not harmful to tissue.

For their study, the researchers ran a series of tests. First, they showed that the drug responded to being triggered by light in cells expressing the adenosine A2A receptor and blocked the receptor.

Then they tested the drug's effect on motor function in live mice. They implanted an optical fiber into the appropriate part of the mice's brains: the striatum.

When they shone light of the correct wavelength down the fiber, the mice showed "significant hyperlocomotion." This treatment also reduced the effect of drug-induced rigidity and tremor.

Finally, they showed that the approach also reversed "motor impairment" in a mouse model of Parkinson's disease.

Remote-controlled 'patch'

Co-corresponding author Dr. Francisco Ciruela, of the Institute of Neurosciences at the University of Barcelona in Spain, explains that there are already treatments for Parkinson's disease that use wires implanted into the brain.

He and his colleagues caution that it is still very early days yet, and that there is a lot of work to do before the light-activated drug is ready for clinical use in a similar way.

Nevertheless, he envisages a future in which the patient has a light-generating "patch" connected to the implanted fiber.

Activation of the light, and thereby the timing of drug release, could be controlled remotely by the doctor through a smartphone app.

Such an approach may also help to minimize dose-timing problems that typically occur in treating long-term illnesses, when commitment to treatment schedules can begin to flag.

"A fine time-space precision will enable manipulating the neural circuits in detail and set the functioning of those with therapeutic and neuroprotective purposes."

Dr. Francisco Ciruela

https://www.medicalnewstoday.com/articles/322097.php

Bacteriophages: Are they an overlooked driver of Parkinson's disease?

June 10, 2018, American Society for Microbiology

Lactococcus

In the first study of its kind, researchers from the New York-based Human Microbiology Institute have discovered the role certain bacteriophages may play in the onset of Parkinson's disease (PD). The research is presented at ASM Microbe, the annual meeting of the American Society for Microbiology, held from June 7th to June 11th in Atlanta, Georgia.

The researchers, led by George, Tetz, M.D., Ph.D., Human Microbiology Institute, showed that the abundance of lytic Lactococcus phages was higher in PD patients when compared to healthy individuals. This abundance led to a 10-fold reduction in neurotransmitter-producing Lactococcus, suggesting the possible role of phages in neurodegeneration. Comparative analysis of the bacterial component also revealed significant decreases in Streptococcus spp. and Lactobacillus spp. in PD.

Lactococcus are regulators of gut permeability and are enteric dopamine producers, which plays a primary role in PD. "The depletion of lactococcus due to high numbers of strictly lytic phages in PD patients might be associated with PD development and directly linked to dopamine decrease as well as the development of gastrointestinal symptoms of PD," said Dr. Tetz.

To explore bacterial and bacteriophage community compositions associated with PD, the researchers used shotgun metagenomics sequencing data of fecal microbiome from 32 patients with PD and 28 controls.

The results indicate that the decrease in Lactococci in the PD patients was due to the appearance of strictly lytic, virulent lactococcal phages belonging to the c2-like and 936 groups that are frequently isolated from dairy products. These results open a discussion on the role of environmental phages and phagobiota composition in health and disease.

"Bacteriophages have previously been overlooked as pathogenic factors, and the study points out their pivotal role in pathogenesis," said Dr. Tetz. Future research is needed to explore bacterial viruses as a diagnostic and treatment target for therapeutic intervention.

Provided by: American Society for Microbiology

https://medicalxpress.com/news/2018-06-bacteriophages-overlooked-driver-parkinson-disease.html

Mutation links bipolar disorder to mitochondrial disease

 June 11, 2018, RIKEN

Abstract rendition of the paper's themes.Mutations in the gene ANT1 may confer a risk for bipolar disorder through a complex interplay between serotonin and mitochondrial signaling in the brain. Credit: Milena Menezes Carvalho/RIKEN National Science Institute

Mutations in the gene ANT1 may confer a risk for bipolar disorder through a complex interplay between serotonin and mitochondrial signaling in the brain. These two pathways have been separately implicated in bipolar disorder, but the link between levels of the neurotransmitter serotonin and mitochondrial dysfunction had not been established. Researchers at the RIKEN Center for Brain Science (CBS) in Japan now report that mitochondrial dysfunction affects the activity of serotonergic neurons in mice with mutations of ANT1.

Mitochondria are the vital organelles that deliver energy to all cells and mitochondrial damage has been found, for example, in brain imaging of bipolar patients and in post-mortem brains. Roughly 20 percent of patients with mitochondrial disease also have bipolar disorder, a major psychiatric disease characterized by manic and depressive episodes. Altered serotonin functioning, on the other hand, seems to be involved in bipolar disorder because drugs that target serotonin levels can effectively treat the condition. "Our study suggests that mitochondrial dysfunction can alter activity of serotonergic neurons in bipolar disorder, and this is the first time these two lines of evidence have been linked," says Tadafumi Kato, research group leader at CBS. The research was published on June 8 in the journal Molecular Psychiatry.

The study started by identifying ANT1 mutations in patients with bipolar disorder. Kato and colleagues then looked at mice lacking the ANT1 gene in the brain only. Compared with non-mutant mice, the mitochondria in these knockout mice could not retain calcium and had leakier pores. The ANT1-mutant mice also showed lower impulsivity in behavior tests, and consistent with this, their brains showed elevated serotonin turnover. This hyper-serotonergic state is likely a result of a cascade of changes that starts with the loss of the ANT1 gene and the resulting dysfunctional mitochondria. Enhanced serotonergic activity may then further impair mitochondria in a vicious cycle.

Immunohistochemical and electrophysiological analysis. (top) whole mouse brain, the dotted region is the dorsal raphe where COX-negative cells were more numerous in the mutants. (botton left). Close-up of the dorsal raphe. COX-negative cells are red. (bottom right) Electrophysiological analysis showed that serotonergic neurons in the mutant dorsal raphe were more excitable than in wildtype mice. Credit: RIKEN National Science Institute

Serotonergic neurons were found to deteriorate in a brain area called the dorsal raphe, which is a region also affected in Parkinson's disease—another condition that may have its roots in mitochondrial dysfunction. The ANT1 mutation does not cause bipolar disorder, says Kato, but is associated with elevated risk. The implication of this research is that emerging therapies for the underlying mitochondrial dysfunction could one day treat bipolar disorder more successfully than today's variable serotonin-targeting drugs.

More information: Tomoaki M. Kato et al, Ant1 mutant mice bridge the mitochondrial and serotonergic dysfunctions in bipolar disorder, Molecular Psychiatry (2018).  DOI: 10.1038/s41380-018-0074-9

Journal reference: Molecular Psychiatry

Provided by: RIKEN

https://medicalxpress.com/news/2018-06-mutation-links-bipolar-disorder-mitochondrial.html

Sensory substitution illuminates cognitive processes while offering therapeutic applications

June 11, 2018, CORDIS

Credit: Monstar Studio, Shutterstock

What are the implications of being able to "listen to a choreography" or "feel a ballet?" Despite the importance of observing the bodily movements of others to understand and predict actions, little is known about the underlying plasticity of the neural mechanism.

The blending of the arts and sciences, traditionally viewed as being somewhat at cross-purposes, has found fertile ground in areas such as education, therapy and rehabilitation. The EU-funded DANCE project found this to be especially true when combined with human-centred computing innovations. 

The DANCE project explored how bodily movement can be expressed and perceived in auditory terms. The project developed technologies which measured the expressive qualities of full-body movement in real-time, translating gestures from visual to auditory phenomena. While contributing to brain-imaging which maps the visual and auditory cortex of blind and sighted people, the approach also offers therapeutic potential, as well as novel human-machine non-verbal interfaces.

Seeing through listening

Research has shown that the sonification (using non-speech audio to convey information) of movement can increase body awareness, along with heightened sensitivity to emotions. This finding has proven useful when applied to therapeutic endeavours.

DANCE brought together performance artists, sound designers, vision and social neuroscientists, computer scientists and engineers to further explore the potential for rehabilitation and increased social inclusion emerging from the sharing of spaces and emotions between visually impaired and sighted people. The EU-funded DANCE team have previously adopted the approach to help patients with Parkinson's disease and those suffering from chronic pain. 

In the project's work, choreographed expressive movement actually creates sonic content in real time. As project coordinator Dr. Antonio Camurri, explains, "This means that dance itself is then conceived as a musical composition, changing its traditional dimension to offer a listening experience rather than principally a visual one."

An overarching theme of the project was to explore the way in which multisensory information runs the risks of creating sensory overload in perceivers. "So instead of augmenting the senses, with the consequent risk of blunting the experience, DANCE proceeded by deliberately creating sensory deprivation as a means of sharpening the senses." Dr. Camurri elaborates. In doing so DANCE also contributed to neuroscience studies looking at brain plasticity.

DANCE conducted a human functional magnetic resonance imaging (fMRI) study investigating the relationship between movement features, obtained from automated computational analyses of video clips, and the brain activity during perception of the videos. 

The results showed that features requiring low-level computation, such as movement speed, map to specific brain areas related to early visual and motion sensitive regions. While mid-level features, such as expressive fluidity, are related to dynamic aspects of posture encoded in different brain areas. 

As Dr. Camurri summarises, "Our computational feature based analysis suggests that the neural mechanism of movement encoding uses features that have a different neural basis from semantic categories. That is, movement perception is organized in the brain not so much by semantic categories, than by features of the body movements themselves."

Choreographing the next steps 

The team developed a technology platform alongside freely available software libraries. These have been adopted for several public events, scientific experiments and mobile applications. A publicly available movement dataset was also created along with prototypes of applications for both blind and non-blind people. 

The project's main public event entitled, "Atlante del gesto Genova' included the participation of blind and sighted people, with an institute for blind people, which took place from November 2016 to March 2017 and has created an on-going community of over 150 participants (including non-specialist members of the public). 

The work can be adapted to generate creative content for therapy and rehabilitation. For example, a new joint laboratory with the Gaslini children's hospital in Italy was created during DANCE. Here, physiotherapists alongside computer engineers and researchers, collaborated in the creation of gaming for rehabilitation. 

DANCE has also been a rich source of inspiration for further research directions such as neuroscientific studies seeking to reveal the underlying neural mechanismsinvolved in the perception of high-level, affective communication through movement, with the aim of creating generation of novel interfaces and applications.

Provided by: CORDIS

https://medicalxpress.com/news/2018-06-sensory-substitution-illuminates-cognitive-therapeutic.html