Is There a Link Between Milk and Parkinson’s Disease?

May 18, 2018

Milk

Parkinson’s is the second most common neurodegenerative disease after Alzheimer’s. Each year in the United States, approximately 60,000 new cases are diagnosed, bringing the total number of current cases up to about a million, with tens of thousands of people dying from the disease every year.

The dietary component most often implicated is milk and contamination of milk by neurotoxins has been considered the “only possible explanation.” High levels of organochlorine pesticide residues have been found in milk, as well as in the most affected areas in the brains of Parkinson’s victims on autopsy. Pesticides in milk have been found around the world, so perhaps the dairy industry should require toxin screenings of milk. In fact, inexpensive, sensitive, portable tests are now available with no false positives and no false negatives, providing rapid detection of highly toxic pesticides in milk. Now, we just have to convince the dairy industry to actually do it.

Others are not as convinced of the pesticide link. “Despite clear-cut associations between milk intake and PD [Parkinson’s disease] incidence, there is no rational explanation for milk being a risk factor for PD.” If it were the pesticides present in milk that could accumulate in the brain, we would assume that the pesticides would build up in the fat. However, the link between skimmed milk and Parkinson’s is just as strong. So, researchers have suggested reverse causation: The milk didn’t cause Parkinson’s; the Parkinson’s caused the milk.

Parkinson’s makes some people depressed, they reasoned, and depressed people may drink more milk. As such, they suggested we shouldn’t limit dairy intake for people with Parkinson’s, especially because they are so susceptible to hip fractures. But we now know that milk doesn’t appear to protect against hip fractures after all and may actually increase the risk of both bone fractures and death. Ironically, this may offer a clue as to what’s going on in Parkinson’s, but first, let’s look at this reverse causation argument: Did milk lead to Parkinson’s, or did Parkinson’s lead to milk?

What we need are prospective cohort studies in which milk consumption is measured first and people are followed over time, and such studies still found a significant increase in risk associated with dairy intake. The risk increased by 17 percent for every small glass of milk a day and 13 percent for every daily half slice of cheese. Again, the standard explanation is that the risk is from all the pesticides and other neurotoxins in dairy, but that doesn’t explain why there’s more risk attached to some dairy products than others. Pesticide residues are found in all dairy products, so why should milk be associated with Parkinson’s more than cheese is? Besides the pesticides themselves, there are other neurotoxic contaminants in milk, like tetrahydroisoquinolines, found in the brains of people with Parkinson’s disease, but there are higher levels of these in cheese than in milk, though people may drink more milk than eat cheese.

The relationship between dairy and Huntington’s disease appears similar. Huntington’s is a horrible degenerative brain disease that runs in families and whose early onset may be doubled by dairy consumption, but again, this may be more milk consumption than cheese consumption, which brings us back to the clue in the more-milk-more-mortality study.

Anytime we hear disease risks associated with more milk than cheese—more oxidative stress and inflammation—we should think galactose, the milk sugar rather than the milk fat, protein, or pesticides. That’s why we think milk drinkers specifically appeared to have a higher risk of bone fractures and death, which may explain the neurodegeneration findings, too. Not only do rare individuals with an inability to detoxify the galactose found in milk suffer damage to their bones, but they also exhibit damage to their brains.

In health,

Michael Greger, M.D.

https://youtu.be/gitX1ZsejJw

https://www.care2.com/greenliving/is-there-a-link-between-milk-and-parkinsons-disease.html

Potential Parkinson’s Vaccine, Affitope PD01A, Safe and Possibly Effective in Long-term, Phase 1 Trial Series Finds

MAY 18, 2018 BY MARTA FIGUEIREDO 

Affiris’ experimental Parkinson’s vaccine, Affitope PD01A, is safe and effectively triggers an immune response against the alpha-synuclein (aSyn) protein, data from a series of four consecutive clinical trials show.

Results from the so-called AFF008 study program were recently presented at the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD) in Torino, Italy, by Werner Poewe, chairman of the Department of Neurology at the Medical University Innsbruck, Austria.

Alpha-synuclein accumulation in nerve cells of the brain leads to the formation of Lewy bodies, spherical masses that replace other cell components. Lewy bodies are thought to underly Parkinson’s symptoms and progression. Therapeutic strategies to reduce alpha-synuclein are expected to beneficially alter the course of this disease.

Affitope PD01A is an experimental vaccine — a synthetic aSyn-mimicking peptide based on Affiris’ Affitome technology — that targets alpha-synuclein by inducing an immune response that generates antibodies specifically against it.

As such, Affitope PD01A has the potential to modify disease progression.

The long-term safety, tolerability, and immune response of Affitope PD01A was evaluated in a series of Phase 1 clinical studies: AFF008 (NCT01568099), AFF008E (NCT01885494), AFF008A (NCT02216188) and AFF008AA (NCT02618941).

The initial AFF008 study, a single-site trial in Vienna, enrolled 32 patients with early Parkinson’s disease. Twenty-four were randomized to receive four subcutaneous (under the skin) injections of Affitope PD01A at one of two doses —  15 μg or 75 μg of Affitope PD01A, once every four weeks for one year in addition to standard treatment. The remaining eight patients remained on standard of care as a comparative control group.

An extension study (AFF008E) then followed AFF008 participants for an additional year with no further investigative treatment. In the AFF008A trial, treated patients were randomized again to receive a single Affitope PD01A injection at either of the two doses to “boost” their immune reaction.

About one year after this “boost,” patients in the treatment groups received a second “boost” — a single injection of 75 μg Affitope PD01A (AFF008AA study). In total, 21 treated and five control group patients completed the entire series of studies.

Data showed that both doses of Affitope PD01A were well-tolerated, with no treatment-associated adverse events other than injection-site reactions, which were considered mild and to have no relation to the administered dose.

Affitope PD01A induced a clear immune response against the peptide itself over time, which effectively translated into an antibody immune response against alpha-synuclein. The first “boost” injection induced a significant increase in the production of specific antibodies, while the second “boost” further stabilized those levels, the researchers reported.

Affitope PD01A-specific antibodies were detected in the cerebrospinal fluid, and at week 26 of treatment there was a trend toward lower levels of oligomeric alpha-synuclein (believed to be one of the most toxic forms of the protein), both in the blood and cerebrospinal fluid of treated patients.

“Immunogenicity results after 4 years of treatment are encouraging and support the hypothesis that long-term disease management by targeting aSyn … with active immunotherapy seems to be feasible,” Poewe said in a press release.

Oliver Siegel, CEO of Affiris, said researchers have further “optimized the formulation of PD01 and immunization schedule …  to improve immunogenicity.”

Although tests included in the AFF008 study series did not show changes in Parkinson’s symptoms with Affitope PD01A treatment, the study was not designed or powered to evaluate its clinical benefit. “Future trials should focus on how to translate the immune response seen in these series of studies into clinical efficacy,” Poewe said.

These studies were funded by a series of grants from The Michael J. Fox Foundation for Parkinson’s Research and from the government agency AWS in Austria.

https://parkinsonsnewstoday.com/2018/05/18/potential-parkinsons-vaccine-affitope-pd01a-shows-promising-long-term-results-in-phase-1-study-series/

How 2 Sets Nerve Cells Interact to Control Movement Seen by Scientists Using New Tool

MAY 18, 2018 BY JOSE MARQUES LOPES, PHD 

Using a new tool, researchers were able to see how two different sets of neurons interact in mice to control movement. They believe the method, called spectrally resolved fiber photometry, may help in unraveling what goes wrong in the brains of Parkinson’s patients and those with other disorders.

The research, “Spectrally Resolved Fiber Photometry for Multi-component Analysis of Brain Circuits,” appeared in the journal Neuron.

Progressive damage to nerve cells in the substantia nigra region of the brain lowers levels of the neurotransmitter dopamine — a chemical responsible for communication between neurons, or nerve cells — and is considered a hallmark of Parkinson’s disease.

Clinical studies in Parkinson’s patients and preclinical research in monkeys suggests that loss of dopamine causes an imbalance in the activity of two groups of neurons: the direct pathway (D1) and indirect pathway (D2). However, this hypothesis could not be confirmed experimentally due an inability to accurately distinguish between these cell types in the brain.

Using spectrally resolved fiber photometry (SRFP), a tool developed at the National Institutes of Health (NIH), researchers in an NIH office labeled D1 and D2 neurons with green and red fluorescent sensors and were then able to effectively follow how they work together in neurons of living mice.

“Our method allowed us to simultaneously measure neural activity of both pathways in a mouse as the animal performed tasks,” Guohong Cui, MD, PhD, the study’s senior author, said in a press release. “In the future, we could potentially use SRFP to measure the activity of several cell populations utilizing various colors and sensors.”

The scientists observed that when activity in D1 was stronger than in D2 neurons, the animals did a “start and go” — starting movement and moving to another location. When D2 neuronal activity was stronger, a mouse does a “start and stop” — it initiates a movement, but stops soon after.

D1 (red) and D2 (green) pathway activity seen 

in the striatum, part of the brain’s 

basal ganglia, in mice. (Photo courtesy of NIEHS)

Both movements are normal in mice and  their analysis may help predict what type of movement will be made based on the neural activity seen. Importantly, being able to trace such activity may help in understanding movement in mouse models of Parkinson’s.

“Based on these observations, we hypothesize that the direct-pathway (D1) activation serves as a movement start signal, and its magnitude determines the vigor of a movement. Meanwhile, the concurrently activated indirect pathway (D2) serves as a scalable stop signal that determines whether the initiated movement will continue or be terminated,” the researchers wrote.

Unlike current methods that cannot distinguish which neurons are generating an electrical output, “SRFP is more specific, because we can distinguish between groups of neurons and see their activity,” said Chengbo Meng, PhD, one of the study’s lead authors.

“We have developed a novel … method for simultaneous multi-color fluorescent signal measurement and unmixing from deep brain structures in vivo,” the study states. “Using this method, we show for the first time that the neural activities of two parallel … pathways are highly synchronized, and the magnitude of activation in these two pathways collaboratively determines the dynamics and fate of movement.”

In addition Parkinson’s disease, the team believes SFRP will contribute to a better understanding of Alzheimer’s, multiple sclerosis, stroke and addiction.

https://parkinsonsnewstoday.com/2018/05/18/new-tool-showing-how-different-neurons-control-movement-may-help-in-parkinsons-studies/

World first use of cognitive training reduces gait freezing in Parkinson's patients

May 18, 2018      UNIVERSITY OF SYDNEY

Research led by the University of Sydney's Brain and Mind Centre, published today npj Parkinson's Disease -- Nature

The researchers report significant reduction in the severity and duration of freezing of gait, improved cognitive processing speed and reduced daytime sleepiness.

Freezing of gait (FoG) is a disabling symptom of Parkinson's Disease, characterized by patients becoming stuck while walking and unable to progress forward, often describing the feeling as being glued to the ground. It is well-known to lead to falls and lower quality of life, making it an important target for treatment. 

Research has linked FoG to aspects of attention and cognitive control, a link supported by neuroimaging evidence revealing impairments in the fronto-parietal and fronto-striatal areas of the brain.

The intervention

Patients with Parkinson's Disease who self-reported FoG and who were free from dementia were randomly allocated to receive either a cognitive training intervention or an active control. 

Sixty-five patients were randomized into the study. The sample of interest included 20 patients randomly assigned to the cognitive training intervention and 18 randomized to the active control group.

Both groups were clinician-led and conducted twice-weekly for seven weeks. The primary outcome was the percentage of time spent frozen during a 'Timed Up and Go' task, assessed while patients were both on and off dopaminergic medications. 

Secondary outcomes included multiple neuropsychological and psychosocial measures, including assessments of mood, well-being and length and quality of sleep.

Results

The researchers report that patients in the cognitive training group showed a large and statistically significant reduction in FoG severity while on dopaminergic medication compared to participants in the active control group on dopaminergic medication.

Patients who received cognitive training also showed improved cognitive processing speed and reduced daytime sleepiness compared to those in the active control while accounting for the effect of dopaminergic medication.

There was no difference between groups when they were tested without their regular dopaminergic medication. 

"We believe there is reason to be hopeful for the use of these trials in the future," said study leader, Dr Simon Lewis, a professor of cognitive neuroscience at the University of Sydney's Brain and Mind Centre and Royal Prince Alfred Hospital in Australia.

"The feedback we've had from participants and family members involved in this study was overwhelmingly positive. The results of this pilot study highlight positive trends, and the importance of nonpharmacological trials involving cognitive training has become increasingly clear."

The research team, comprising scholars from the University of Sydney, Western Sydney University and Cambridge University say the finding that freezing of gait improved only while patients were on dopaminergic medication is noteworthy. 

"Taking dopaminergic medications as prescribed is the normal day-day state for patients with Parkinson's Disease," said study lead-author, Dr Courtney Walton, formerly at the University of Sydney and now at the University of Queensland.

"While more research is needed to better understand and establish these findings, it's likely that participants in the off- dopaminergic state were too impaired to benefit from any of the potential changes initiated through cognitive training."

The researchers say more studies using larger samples are needed to investigate this initial finding that cognitive training can reduce the severity of freezing of gait in Parkinson's diseases patients.

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Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

https://www.eurekalert.org/pub_releases/2018-05/uos-wfu051818.php

Microglia are key defenders against prion diseases

May 17, 2018, NIH/National Institute of Allergy and Infectious Diseases

Microglia, shown in green, are part of the immune response that protect the brain. They could play a role in slowing the progress of prion and other neurodegenerative diseases. Credit: NIAID

Prion diseases are slow degenerative brain diseases that occur in people and various other mammals. No vaccines or treatments are available, and these diseases are almost always fatal. Scientists have found little evidence of a protective immune response to prion infections. Further, microglia—brain cells usually involved in the first level of host defense against infections of the brain—have been thought to worsen these diseases by secreting toxic molecules that can damage nerve cells.

Now, scientists have used an experimental drug, PLX5622, to test the role of microglia against scrapie, a prion disease of sheep. PLX5622 rapidly kills most of the microglia in the brain. When researchers gave the drug to mice infected with scrapie, microglia were eliminated and the mice died one month faster than did untreated mice. The results, published in the Journal of Virology by researchers from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, suggest that microglia can defend against a prion infection and thus slow the course of disease. The scientists hypothesize that microglia trap and destroy the aggregated prion proteins that cause brain damage.

The findings suggest that drugs that increase the helpful activity of microglia may have a role in slowing the progression of prion diseases. Researchers are now studying the details of how microglia may be able to destroy prions in the brain. The scientists note that microglia could have a similar beneficial effect on other neurodegenerative diseases associated with protein aggregation, such as Alzheimer's disease and Parkinson's disease.

More information: James A. Carroll et al, Microglia Are Critical in Host Defense Against Prion Disease, Journal of Virology (2018).  DOI: 10.1128/JVI.00549-18 

Journal reference: Journal of Virology

Provided by: NIH/National Institute of Allergy and Infectious Diseases 

https://medicalxpress.com/news/2018-05-microglia-key-defenders-prion-diseases.html

New study sheds light on brain's ability to orchestrate movement

May 17, 2018, Harvard Medical School

To carry out any action, whether playing the piano or dancing the jitterbug, the brain must select and string together a series of small, discrete movements into a precise, continuous sequence.

How exactly the brain achieves this remarkable feat has been a mystery, but a new study in mice, led by scientists from Harvard Medical school, brings much needed insight into this process.

Results of the study, published online May 17 in Cell, reveal that the brain relies on an exquisite balance between the activity of two populations of neurons in a part of the brain called the striatum, the coordinating center for motor and action planning. The findings could help researchers better understand conditions that dramatically impact movement—such as Parkinson's disease and Huntington's disease—and eventually develop new ways to treat them.

"We believe our observations set the stage for both unraveling how movement gets translated into desired action, and propel us forward in our ability to understand and, eventually, treat devastating neurodegenerative disorders where this process goes awry," said the study's senior author Sandeep Robert Datta, associate professor of neurobiology at Harvard Medical School.

Scientists have long known that the striatum, a spiral-shaped region buried in the forebrain, is a critical component of the motor system, which houses the neurons that die out in both Parkinson's and Huntington's diseases.

Previous research identified two populations of cells in the striatum—spiny projection neurons arranged into what are called the direct and the indirect pathways—that control key aspects of movement.

However, precisely how these two pathways interact to modulate and guide movement has remained unclear. Some evidence suggests that the direct pathway selects and initiates the expression of actions, while the indirect pathway inhibits unwanted actions. Other studies, however, have found that both pathways are often activated at the same time.

"That didn't make sense based on what we've long thought each pathway did," explained the study's lead author Jeffrey Markowitz, a postdoctoral fellow in the department of Neurobiology.

To better define the dynamic between these pathways, the research team took advantage of technology developed by the Datta lab called MoSeq, short for motion sequencing. The system films animals' three-dimensional movements and uses machine learning to fine-splinter, or precisely parse, the movements into basic patterns lasting only a few hundred milliseconds apiece. The researchers dubbed those ultra-fast movements "syllables."

Teaming up with neural imaging experts from Bernardo Sabatini's lab, the researchers genetically altered neurons in the direct and indirect pathways to fluoresce, or glow, in different colors when activated. Combining neural imaging, genetic engineering and MoSeq allowed the scientists to observe and analyze the neural activity simultaneously in both pathways as mice performed a variety of actions.

Corroborating previous studies, the researchers found that every time mice switched behaviors—from running to stopping, for example—the activity of both pathways increased.

When they looked at syllables identified by MoSeq, however, they found that the balance of activity between the two pathways differed. For some syllables, the direct pathway dominated; for others, the indirect pathway did. Even for highly similar syllables, such as two different types of "scrunching," or curling up in a ball, the two pathways could be distinguished. Each syllable yielded a particular balance between the two pathways. The relationship between neural activity and syllables was so pronounced that the researchers could successfully identify specific syllables expressed based on the pathway activity alone.

The activity ratios between the pathways were so constant that the researchers successfully identified specific syllables being expressed based on the activity of the pathways alone. Using imaging techniques, they could also observe ensembles of neurons that displayed regular and predictable patterns of activity during particular syllables.

In a final set of experiments, the scientists wanted to understand what happened when activity in these pathways was disrupted or went awry. To do so, they induced lesions in the striatums of a handful of mice. After a week of recovery, they placed the mice into an arena-like space that had the scent of a fox wafting through one side. With an inborn instinct to avoid predation, mice with an intact striatum immediately raced to the other side of the arena. Mice with lesions in their striatums were also able to display all the separate syllables seen in normal mice, such as sniffing, running, rearing and turning, but their brains somehow failed to sequence these movements correctly rendering the animals incapable of reaching the arena's opposite side.

"This underscores the importance of order in piecing movements together toward a desired outcome," Datta said. "Even if you're able to move your body correctly, if you can't put actions in the correct order, it's hard to do even the most basic of things."

If replicated in further studies, the findings could help inform new treatments for Parkinson's disease and Huntington's disease, conditions in which even basic movements become extremely difficult as these diseases progress, the researchers said.

Currently, Parkinson's disease is treated by giving patients a form of the neurotransmitter dopamine, which stimulates both the direct and indirect pathways. However, the efficacy of the treatment wanes over time. There is still no effective treatment for Huntington's disease.

"We hope that future work emanating from these findings would address more specifically what exactly happens in these cell types when neurodegenerative disorders rob people's brains of their ability to generate actions and action sequences," Datta said.

Journal reference: Cell 

Provided by: Harvard Medical School

https://medicalxpress.com/news/2018-05-brain-ability-orchestrate-movement.html

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Almost two years later, medically assisted dying remains complicated, experts say

May 17, 2018, University of Toronto

As a journalist, Maureen Taylor remembers covering the case of Sue Rodriguez, who was denied assisted suicide through a Supreme Court decision in 1993. At the time, Taylor couldn't have imagined that 10 years later she'd be surreptitiously investigating a way to help her own husband, Dr. Donald Low, take his life.

After a terminal cancer diagnosis in 2013, the University of Toronto professor and infectious disease specialist longed for control over how and when he would die. Frustrated at not having that choice, Low made a compelling case for the right to assisted dying in a widely viewed video, released after his death.

Taylor – who had already transitioned from award-winning health journalist to physician assistant – took on yet another vocation: assisted dying advocate. She co-chaired an expert panel making recommendations to government and has spoken out publicly for changes in legislation.

She recently joined U of T physicians, educators and researchers at a Faculty of Medicine event called UofTMedTalks, where they delved into how end-of-life care is changing in the era of medical assistance in dying.

"It's been almost two years since Canadians have had the right to discuss assisted dying with a health-care provider, but how is the system working?" Taylor asks. "How easy is it to navigate, for patients and for health-care providers?"

It's complicated, was the resounding consensus.

As medical assistance in dying has shifted from controversial debate to constitutional right, there's a clear need for more research and education to address gaps in knowledge and access, especially for the broader field of palliative care, the speakers said.

One of the big surprises was the unease among many palliative care specialists to be involved in medical assistance in dying. Having worked hard to counter the misconception that palliative care hastens death, many of these specialists found this new function at odds with their practice.

"Medical assistance in dying is 100 per cent palliative care," says Jeff Myers, an associate professor in U of T's Faculty of Medicine, "and at the exact same moment it's 180 degrees opposite of palliative care."

Myers – the W. Gifford-Jones Professor in Pain Control and Palliative Care, head of the division of palliative care in the department of family and community medicine and site lead at Sinai Health System's Bridgepoint Palliative Care Unit – is focused on reconciling this contrast.

"Now in Canada, the end-of-life part of palliative care is inextricably linked with medical assistance in dying," he says. He shared his own recent experiences providing the procedure, and reflected on the hope and relief it offered patients.

For Sandy Buchman, an associate professor in the department of family and community medicine, it was that relief from suffering that convinced him to provide medical assistance in dying. As a family and palliative care physician with the Sinai Health System's Temmy Latner Centre for Palliative Care, Buchman cares for patients at end of life, in their homes.

Buchman didn't set out to provide medical assistance in dying – or even palliative care before that. As a family physician, it was patients with HIV/AIDS who introduced him to the field of palliative care. And more recently, as he was grappling with the decision of whether he would provide medical assistance in dying when it became legal, a patient and U of T professor and cardiologist who suffered from advanced Parkinson's asked if Buchman would help.

"Just the hope that MAiD [medical assistance in dying] offered him was incredible to me," he says. "I went into medicine to relieve suffering."

Buchman came to consider medical assistance in dying as consistent with these values.

It's not the only way to relieve suffering, however, stresses Buchman. When patients are given other options to manage pain and reduce suffering – core goals of palliative care medicine – many will no longer request medical assistance in dying.

This is one of the frustrations in the palliative care community: With so much attention on medical assistance in dying, some feel that unmet needs in palliative medicine continue to be overlooked.

"MAiD is only a choice if there's another option," says Myers, who worries that not enough Canadians have access to palliative care. He hopes the spotlight shining on medical assistance in dying will help illuminate the broader field of end-of-life care.

Already, researchers and palliative care specialists like Professor Camilla Zimmermann have been transforming our understanding of the field. A professor in the departments of medicine and psychiatry and palliative care physician and senior scientist at the University Health Network's Princess Margaret Cancer Centre, Zimmermann holds the Rose Family Chair in Palliative Medicine and Supportive Care. She has shown how early access to palliative care – starting at the time of diagnosis – leads to greater quality of life.

While she recognizes there wouldn't be enough palliative care specialists for every patient in need, she believes education is key. She says we should be training all medical students and many specialists in providing some level of palliative care.

"If you're a specialist in lung cancer," she gives as an example, "you should really know how to treat shortness of breath."

While much remains to be done, there's been major progress, in both palliative medicine education and in medical assistance in dying. Just last year, Zimmermann and Myers have helped launch a new Royal College subspecialty training program in palliative medicine at U of T. And researchers and educators have been developing guidelines and best practices about medical assistance in dying.

"It is in complex areas like this that knowledge, expertise and passion, become so essential," says Faculty of Medicine's Executive Director of Advancement Darina Landa, who hosted the event.

Maureen Taylor still has questions, both in her role as a health-care provider, and advocate: "If a patient doesn't bring MAiD up as an option, can I? Is that appropriate?"

Provided by: University of Toronto

https://medicalxpress.com/news/2018-05-years-medically-dying-complicated-experts.html

Living drug factories” may one day replace injections

May 16, 2018   Rob Matheson 

MIT spinout Sigilon Therapeutics has partnered with pharmaceutical giant Eli Lilly and Company to develop implantable medical devices that act like “living drug factories,” encapsulating engineered cells that live in the body for months, or years, and produce insulin. Down the road, cells may also be engineered to secrete other hormones, proteins, and antibodies.

Patients with diabetes generally rely on constant injections of insulin to control their disease. But MIT spinout Sigilon Therapeutics is developing an implantable, insulin-producing device that may one day make injections obsolete.

Sigilon recently partnered with pharmaceutical giant Eli Lilly and Company to develop “living drug factories,” made of encapsulated, engineered cells that can be safely implanted in the body, and produce insulin over the course of months or even years. Down the road, cells may also be engineered to secrete other hormones, proteins, and antibodies.

The technology at Sigilon — based on research performed over the last decade at MIT — has led to creation of a device that encases cells and protects them from the patient’s immune system. This can be combined with engineered cells that produce a target therapeutic, such as insulin. The devices are tiny hydrogel beads, about 1 millimeter in diameter, that can be implanted into the patient through minimally invasive procedures.

“This allows us to have ‘living drug factories’ inside our bodies that can deliver therapeutics, at the right amount and in the right location, as needed,” says co-founder and co-inventor Daniel G. Anderson, an associate professor in MIT’s Department of Chemical Engineering, Institute for Medical Engineering and Science, and Koch Institute For Integrative Cancer Research. “The hope is that this living device can be placed in a patient, avoid the need for immune-suppression, and provide long-term therapy.”

Sigilon’s other co-founders and co-inventors are Robert Langer, the David H. Koch Institute Professor at MIT; José Oberholzer, a researcher and surgeon, director of the Charles O. Strickler Transplant Center, and professor of surgery and biomedical engineering at the University of Virginia; Arturo Vegas, a former MIT postdoc and now a professor of chemistry at Boston University; and Omid Veiseh, a former MIT postdoc and now a professor of bioengineering at Rice University.

Finding the right material

Today, most patients with diabetes will prick their fingers several times a day to draw blood and test blood-sugar levels. When needed, they’ll inject insulin. It’s an effective treatment but is often dosed incorrectly, leading to uncontrolled blood sugar levels. “Even the most careful, hard-working diabetics have trouble doing it right, so they will often find their blood sugar is too high or too low,” Anderson says.

Another promising treatment, called cell therapy, has been around for decades. In this treatment, a patient receives transplanted human cells that secrete a protein, hormone, or other agent that’s needed to fight a disease or that the patient’s bodies can’t produce. Patients with diabetes, for instance, receive transplanted pancreatic beta cells, from cadavers, which sense blood sugar levels and produce insulin in response.

Some patients using this approach get long-term control of blood-sugar levels, and no longer need to inject insulin, Anderson says. However, these patients have to take immune suppressants, or their immune systems will reject and kill the foreign cells.

In more recent years, researchers have focused on cell encapsulation, surrounding transplanted cells in a thin polymer film to ward off the immune response but still nourish the cells. Such therapies have shown potential to treat cancer, heart failure, hemophilia, glaucoma, and Parkinson’s disease, among other diseases and conditions. But, so far, no treatments have made it to market.

In the mid-2000s, Julia Greenstein of the Juvenile Diabetes Research Foundation (JDRF) reached out to the MIT team for help developing new technological approaches toward islet cell encapsulation. This collaboration resulted in funding from JDRF and the Leona M. and Harry B. Helmsley Charitable Trust to MIT and Children’s Hospital Boston, to develop commercially viable cell-encapsulation technology for diabetes.

The issue was identifying the right material that protected cells but made them, essentially, invisible to the immune system. Most materials placed in the body lead to scar tissue accumulation, a process called “fibrosis.” When medical devices are covered in scar tissue, for instance, they become isolated from the body, which can block transfer of insulin and cause encapsulated cells to die.

The answer was to chemically modify alginate, a polysaccharide that lines the cell walls of brown algae. When combined with water, alginate can also be made into a gel that can safely encapsulate cells without limiting function. However, the researchers had to ensure the coating would not cause fibrosis. To do so, they attached different molecules to the alginate’s polymer chain, chemically modifying the structure hundreds of times until they found a version that didn’t provoke an immune response.

The end result: “A hydrogel that keeps cells alive and is permeable so that sugar and nutrients can come in and insulin can come out, but still blocks cellular elements of the immune system, like T cells, which can destroy the therapeutic cells inside,” Anderson says.

In three studies, published in Nature Materials in 2015 and in Nature Medicine and Nature Biotechnology in 2016, the researchers implanted cells encapsulated in their hydrogel into animals. They found the cells immediately produced therapeutic amounts of insulin in response to blood sugar levels and kept blood sugar under control over the course of a six-month study. They also found that small capsules of the hydrogel implanted in the subjects, which didn’t contain engineered cells, prevented fibrosis.

“There had been a growing collection of scientific work, taking different approaches to this problem,” Anderson says. “The key challenge was finding materials that avoid scar tissue formation.”

Just the beginning

Langer and Anderson launched Sigilon to commercialize the technology by setting up Sigilon headquarters in Cambridge, Massachusetts, with more than $23 million in venture capital.

In early April, Sigilon partnered with Lilly, a worldwide leader in diabetes care, to use Sigilon’s encapsulation technology, called Afibromer, to develop a treatment for type 1 diabetes. Under the agreement, Sigilon will receive an upfront payment of $63 million, an equity investment, and more than $400 million in milestone payments to take the Afibromer devices containing stem-cell-derived pancreatic beta cells through clinical trials.

But that’s just the beginning, Anderson says. “Lilly is a major player in diabetes treatment, and we will take this forward [to treat diabetes],” he says. “But we see this as technology that can be used for many applications.”

Sigilon is working on various other applications, including “sense and respond” therapies, where cells sense biological signals and respond with precise dosage of a target therapeutic. Engineered cells could, for instance, secrete proteins to treat lysosomal storage diseases, where patients lack enzymes to break down lipids or carbohydrates; treat hemophilia with hormone release; or respond to inflammatory mediators with anti-inflammatory proteins.

In the future, Sigilon’s polymer could also be modified as a coating for implanted medical devices, such as coronary stents or insulin pumps. “Wires and shunts and pumps all have problems with scar tissue formation,” Anderson says. “The more we connect things with the body, the more important it will be to have materials that can avoid fibrosis.”

http://news.mit.edu/2018/sigilon-therapeutics-living-drug-factories-insulin-diabetes-0517

Researchers identify gene that helps prevent brain disease

May 16, 2018, University of California - San Diego

Image reveals Purkinje cells (gray) and their dendrites, as well as an accumulation of protein deposits (red dots). Credit: Ackerman Lab/UC San Diego

Scientists know that faulty proteins can cause harmful deposits or "aggregates" in neurological disorders such as Alzheimer's and Parkinson's disease. Although the causes of these protein deposits remain a mystery, it is known that abnormal aggregates can result when cells fail to transmit proper genetic information to proteins. University of California San Diego Professor Susan Ackerman and her colleagues first highlighted this cause of brain disease more than 10 years ago. Now, probing deeper into this research, she and colleagues have identified a gene, Ankrd16, that prevents the protein aggregates they originally observed.

Usually, the information transfer from gene to protein is carefully controlled—biologically "proofread" and corrected—to avoid the production of improper proteins. As part of their recent investigations, published May 16 in the journal Nature, Ackerman, Paul Schimmel (Scripps Research Institute) My-Nuong Vo (Scripps Research Institute) and Markus Terrey (UC San Diego) identified that Ankrd16 rescued specific neurons—called Purkinje cells —that die when proofreading fails. Without normal levels of Ankrd16, these nerve cells, located in the cerebellum, incorrectly activate the amino acid serine, which is then improperly incorporated into proteins and causes protein aggregation.

"Simplified, you may think of Ankrd16 as acting like a sponge or a 'failsafe' that captures incorrectly activated serine and prevents this amino acid from being improperly incorporated into proteins, which is particularly helpful when the ability of nerve cells to proofread and correct mistakes declines," said Ackerman, the Stephen W. Kuffler Chair in Biology, who also holds positions in the UC San Diego School of Medicine and the Howard Hughes Medical Institute.

Proofreading defect bypassed. Credit: Ackerman Lab/UC San Diego

The levels of Ankrd16 are normally low in Purkinje cells, making these neurons vulnerable to proofreading defects. Elevating the level of Ankrd16 protects these cells from dying, while removing Ankrd16 from other neurons in mice with a proofreading deficiency caused widespread buildup of abnormal proteins and ultimately neuronal death.

The researchers describe Ankrd16 as "...a new layer of the machinery essential for preventing severe pathologies that arise from defects in proofreading."

The researchers note that only a few modifier genes of disease mutations such as Ankrd16 have been identified and a modifier-based mechanism for understanding the underlying pathology of neurodegenerative diseases may be a promising route to understand disease development.

More information: ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase, Nature(2018). nature.com/articles/doi:10.1038/s41586-018-0137-8 

Journal reference: Nature

Provided by: University of California - San Diego

https://medicalxpress.com/news/2018-05-gene-brain-disease.html