New developments for the treatment of muscle spasticity after stroke and nervous system defects

Chronic muscle spasticity after nervous system defects like stroke, traumatic brain and spinal cord injury, multiple sclerosis and painful low back pain affect more than 10% of the population, with a socioeconomic cost of about 500 billion USD. Currently, there is no adequate remedy to help these suffering people, which generates an immense medical need for a new generation antispastic drugs.

András Málnási-Csizmadia, co-founder of Motorpharma Ltd. and professor at Eötvös Loránd University in Hungary leads the development of a first-in-class drug candidate co-sponsored by Printnet Ltd. MPH-220 directly targets and inhibits the effector protein of muscle contraction, potentially by taking one pill per day. By contrast, current treatments have low efficacy and cause a wide range of side effects because they act indirectly, through the nervous system.

“We receive desperate emails from stroke survivors, who suffer from the excruciating symptoms of spasticity, asking if they could participate in our research. We work hard to accelerate the development of MPH-220 to alleviate these people’s chronic spasticity,” said Prof. Málnási-Csizmadia.

The mechanism of action of MPH-220 and preclinical studies are recently published in Cell. Dr. Máté Gyimesi, CSO of Motorpharma Ltd. highlighted: “The scientific challenge was to develop a chemical compound which discriminates between skeletal and cardiac muscle myosins, the motor proteins of these contractile systems. This feature of MPH-220 makes it highly specific and safe.”

Prof. James Spudich, co-founder of Cytokinetics, MyoKardia and Kainomyx, all companies developing drugs targeting cytoskeletal components, is also very excited about MPH-220 as a possible next generation muscle relaxant. “Cytokinetics and MyoKardia have shown that cardiac myosin is highly druggable, and both companies have potential drugs acting on cardiac myosin in late phase clinical trials. Skeletal myosin effectors, however, have not been reported. Motorpharma Ltd. has now developed a specific inhibitor of skeletal myosin, MPH-220, a drug candidate that may reduce the everyday painful spasticity for about 10% of the population that suffers from low back pain and neurological injury related diseases,” said Professor Spudich, former chair of Stanford medical school’s Biochemistry department, a Lasker awardee.

Drug development specifically targeting myosins is becoming a distinguished area, as indicated by last week’s acquisition of MyoKardia by Bristol-Myers Squibb Co. for 13.1 billion dollars in an all-cash deal, in the hope of marketing their experimental heart drug targeting cardiac myosin. This business activity shows the demand for start-up biotech companies such as Myokardia or Motorpharma.

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How to boost your immune system in good time for flu season

Already starting to panic about flu season? You’re not alone.

Do you need a flu jab? How can you tell the difference between flu symptoms and coronavirus? How can you boost your immune system ahead of winter?

There has been an intense focus on health and immunity this year thanks to Covid-19 and now everyone’s starting to think about how best to protect themselves for the winter.

‘The immune system is one of the most complex and comprehensive systems in the human body,’ says Mike Wakeman, a clinical pharmacist and ambassador for health food supplement CurraNZ.

‘It’s also one of the most important. It’s the invisible barrier against all sorts of foreign assaults from micro-organisms (fungal infections, bacteria and Covid-19) and allergens (pollens, dust mites and chemicals) that we encounter on a daily basis.’

Our first level of immunity is called the innate immune system and is activated as soon as a disease-causing micro-organism is detected. It can detect invaders such as viruses, bacteria, parasites and toxins and attempt to kill them off, before they can enter the body.

‘Innate immunity is made up of things like skin, the gastrointestinal tract and the respiratory tract. Inside these parts of the body are barriers like mucus, secretion and gastric acid, which try to stop the invaders getting in. The innate system also has immune cells (called macrophages), which are some of the most abundant cells in the human body and specialise in detecting and destroying bacteria and other harmful organisms by engulfing and killing them,’ says Mike.

The second level of protection is called the adaptive immune system, which is activated to enhance the innate system.

‘This is mainly cells called lymphocytes,’ explains Mike. ‘They are a type of white blood cell that have the ability to recognise a unique part of a micro-organism, memorise it and produce specific pathogen-neutralising compounds known as immunoglobulins. So when the body encounters this particular antigen [foreign substance] again it can produce more of the immunoglobulins it knows can kill it. This is the basis of how immunisations and flu jabs work.’

Generally, our immune system does an amazing job of defending us but a recent review in the Journal of Sport and Health Science found that ageing, obesity, and inactivity have a negative effect on the immune system.

‘The idea of boosting your immunity sounds like a simple enough process, but it’s not like giving yourself an injection or taking a shot,’ says Mike.

‘You need to think more about optimising your immunity on a daily basis as some vitamins and minerals take longer to generate their effect than others. Vitamin C is water soluble so absorbed straight away, while vitamin D is fat-soluble so is stored in fat cells rather than circulating in the body.

‘Autumn is the best time to think about how to build up immunity for winter and a good quality multi-vitamin is a cheap way to start optimising your protection.’

Spot the signs of a weakened immune system

Don’t wait until you become poorly to start looking after yourself – if you are suffering from any of these problems it’s worth taking stock and taking some extra care, says Mike.

Spot the signs

Cracks in the corner of the mouth

‘This can indicate some aspects of the immune system might be under stress. Vitamins and minerals are vital as they can help to resolve minor issues like this.’

Constant cold symptoms or infection

‘Constant and repeated colds are not only a sign of a weakened immune system, but also place extra demands on immune micronutrient status.’

Wounds take longer to heal

‘Poor healing is a typical symptom of a challenged immune system, and a number of vitamins, such as vitamin C can help improve the skin function.’

Bleeding gums

‘Often poor oral hygiene can be a major challenge to the immune system, so brush your teeth regularly, twice daily and don’t forget to floss.’

Constantly tired and over-stressed

‘Stress can really impact on our immune function, so take time out to look after yourself, get some exercise and relieve stress and exhaustion as much as possible.’

A weakened immune system can be helped with simple diet changes. ‘Most of us are deficient in vitamin D which is produced by the body when we’re exposed to sunshine,’ says Mike.

‘We don’t get enough of it during the summer and definitely not in winter. Oily fish, like pilchards, sardines, mackerel and some salmon are a good source of vitamin D and also high in omega-3 fatty acids, which may also help enhance the function of the immune cells.’

Mike is keen to emphasise that lots of what you need to bolster the immune system can be found in food. ‘You should be eating at least five portions of fruit and veg a day,’ he says.

‘Not only do vitamins and minerals optimise the immune system, they have an anti-inflammatory effect too, so if the immune system over-responds, these micronutrients can help resolve the inflammation this causes. These vitamins and minerals also help the body produce anti-bacterial compounds that fight infection within the body while compounds known as polyphenols support immunity.’

So, a healthy diet has never been more important. When teamed with a good quality multi-vitamin you should stand a better chance of fighting off the winter nasties.

Supplements to help boost your immune system

Five of the best supplements to give a helping hand

1. Extra special

Vitabiotics Immunace Extra Protection contain lycopene, resveratrol, astaxanthin, alpha lipoic acid and vit D. £10.15 (30 tablets)

2. Gum deal

Sambucol ImmunoForte Gummies contain black elderberry flavonoids, plus vitamin C, zinc and high levels of antioxidants. Suitable for vegans. £11 (30 gummies)

3. Vit blitz

Urgent-C Everyday Immune Support contains 1,000mg of vitamin C, plus vitamin D, zinc, selenium, beta glucans and elderberry extract which all help the normal function of the immune system. £14.95 (30 sachets)

4. Berry nice

Blackcurrants offer anti-viral and anti-microbial properties to help the body ward off infection. A single capsule of CurraNZ is equivalent to a handful of berries. £21.75 (30 capsules)

5. Sweet Treat

Made with all-natural ingredients and boosted with 100 per cent NRV vitamin D, C and B12, these new Perkier +Immune bars are tasty plant-based snacks to boost immune health. £15.99 (15 bars)

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Memory training for the immune system

After an infection of the human body with a pathogen, a cascade of reactions will usually be set into motion. Amongst others, specific cells of the immune system known as T cells get activated in the lymph node and will subsequently divide and proliferate.

At the same time, these cells will gain certain functions, that enable them to destroy other cells, that are e.g. infected by a virus. In addition, they produce certain proteins—so called cytokines—with which they can stop the reproduction of the pathogen.

The immune system and its function are the main focus of the research of Professor Wolfgang Kastenmueller, director of the Chair of Systems Immunology I at the Institute of Systems Immunology of the Julius-Maximiliams-Universität Würzburg (JMU). Together with Professor Georg Gasteiger, director of the Chair of Systems Immunology II, they lead the Max-Planck Research group of Systems Immunology.

Their research focus is the interaction of the immune system with the organism, especially the interaction of different cells of the immune system within local networks and with other cells of other organ systems.

Recently Kastenmueller and his team deciphered new details of the functioning of the immune system, which are important for the immune system to remember recent infections. Their results have been published in the latest issue of the scientific journal Nature Immunology. Their findings could help to improve immune therapy towards tumor diseases.

“If a body has fought and eliminated a pathogen successfully, most of the recently proliferated T cells are no longer needed and will die,” Wolfgang Kastenmueller explains. But about five to ten percent of these cells survive and develop into a long lasting “memory population,” that will protect the body against future infections.

Improvement of the immunological memory

Kastenmueller describes the main result of his study, “In our recent work we identified a transcription factor—BATF3, that very specifically regulates the survival of these cells and therefore the transition into a memory response.” The scientists could show that this factor only gets produced shortly after the initial activation of T cells. The absence of this factor leads to a permanent malfunction of the memory response.

Until now the role of this factor for so-called CD8+ T cells was unclear. It was only after the scientists overexpressed this factor in CD8+ T cells that the importance became clear, as they could see that the survival of these cells and thus the immunological memory improved significantly.

This study was conducted in close collaboration with the Medical Clinic II of the University clinic of Wuerzburg. It combines basic research with applied medicine and could help to develop better therapies for cancer treatments that use the immune system of the patient—so-called CAR-T cell therapy.

Using CAR-T cell therapy, T cells get extracted from the blood of the patient and are subsequently genetically modified with the chimeric antigen receptor (CAR) molecules. This modification enables T cells to attack tumor cells, which they couldn’t biochemically detect before. These modified T cells are subsequently transferred back into the patient.

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New connections reveal how cancer evades the immune system

If cancer is a series of puzzles, a new study pieces together how several of those puzzles connect to form a bigger picture.

One major piece is the immune system and the question of why certain immune cells stop doing their job. Another piece involves how histones are altered within immune cells. A third piece is how a cell’s metabolism processes amino acids.

“Nobody knew if those questions were all connected. We were able to place several of these puzzles together and see how it works,” says Weiping Zou, M.D., Ph.D., Charles B. de Nancrede and a Professor of Surgery, Pathology, Immunology and Biology at the University of Michigan and director of the Center of Excellence for Immunology and Immunotherapy at the U-M Rogel Cancer Center.

Zou is senior author on a paper published in Nature that includes multiple labs from the Rogel Cancer Center and collaborators from Poland.

The study found a connection between these three separate puzzles that suggests targeting the amino acid methionine transporter in tumor cells could make immunotherapy effective against more cancers.

It starts with T cells, the soldiers of the immune system. Cancer can turn these cells abnormal, preventing T cells from mounting an attack against it. The question is: what causes this?

Researchers looked at the tumor microenvironment, specifically how tumors metabolize amino acids. They found an amino acid called methionine had the most impact on T cell survival and function. T cells with low levels of methionine became abnormal. Low methionine in the T cells also altered histone patterns that caused T cells to be impaired.

Introducing tumor cells to the picture creates a fight between the tumor cells and the T cells for methionine. Over and over, the tumor cells win, taking the methionine from the T cells and rendering them ineffective.

Previous research has considered a systemic approach to starve tumor cells of methionine, with the idea that the tumor cells are addicted to it. But, Zou says, this study shows why that approach may be a double-edged sword.

“You have competition between tumor cells and T cells for methionine. The T cells also need it. If you starve the tumor cells of methionine, the T cells don’t get it either. You want to selectively delete the methionine for the tumor cells and not for the T cells,” Zou says.

In fact, the study found that supplementing methionine actually restored T cell function. High enough levels of methionine meant there was enough for both tumor cells and T cells.

One key is that tumor cells have more of the transporters that deliver methionine. The researchers found that impairing those transporters resulted in healthier T cells as the T cells could compete for methionine.

Zou was awarded a $3.2 million grant from the National Cancer Institute to advance this work.

“There are still a lot of mechanistic details we have not worked out, particularly the detailed metabolic pathways of methionine metabolism. We also need to understand how metabolism pathways may be different from tumor cells and T cells. We hope to find a target that is relatively specific to tumor cells so that we do not harm the T cells but impact the tumor,” Zou says. This work will be the focus of the new grant.

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Pseudoislet system expected to advance pancreas and diabetes research

The multicellular, 3-D structure of human pancreatic islets—the areas of the pancreas containing hormone-producing or endocrine cells—has presented challenges to researchers as they study and manipulate these cells’ function, but Vanderbilt University Medical Center researchers have now developed a pseudoislet system that allows for much easier study of islet function.

A pancreatic islet is composed primarily of beta cells, alpha cells and delta cells, but also includes many supporting cells, such as endothelial cells, nerve fibers and immune cells, which act in concert as a mini organ to control blood glucose through hormone secretion. Insulin, secreted from beta islet cells, lowers blood glucose by stimulating glucose uptake in peripheral tissues, while glucagon, secreted from alpha islet cells, raises blood glucose through its actions in the liver.

Dysfunction of these islet cells is a primary component of all forms of diabetes, and a better understanding of this dysfunction can lead to improved treatment and management of the disease. Vanderbilt scientists and others around the world have identified potential targets for diabetes using both mouse models and human tissue, however the lack of a system to manipulate these pathways in human islet cells has limited the field.

The VUMC team led by Marcela Brissova, Ph.D., research professor of Medicine and director of the Islet Procurement and Analysis Core of the Diabetes Research and Training Center, began attempting a protocol for the pseudoislet system in 2016, performing countless trials. In late 2017, Rachana Haliyur, then a Vanderbilt MD/Ph.D. student, combined media containing factors that support vascular cells and endocrine cells into what the group named the Vanderbilt Pseudoislet Media. The team watched as the cells began reaggregating, or organizing themselves in a way that resembled native islets.

“A lot of things in science happen serendipitously, and this was one of those,” said Brissova. “We tried and failed many times, and basically it came down to the media we used for our cells. In our recent publication, we have provided all experimental details and our protocol so others can make the media and create pseudoislets in their own laboratories.”

Because of the complex structure of the human islet, it is difficult to introduce and manipulate cells past the first cell-layer of the islet sphere. The pseudoislet system allows investigators to separate the pancreatic islet into single cells, introduce a virus into the cells which allows genetic manipulation and then combine the cells back together again into a pseudoislet. This allows researchers to target certain cell types or replicate changes happening in disease and study them in the 3-D environment of the islet.

John “Jack” Walker, an MD/Ph.D. student in the Powers & Brissova Research Group, continued to refine the pseudoislet system protocol and was co-first author on a recent study based on the system published in JCI Insight, an open access journal published by the American Society for Clinical Investigation (ASCI).

The pseudoislet system allowed the VUMC investigators to more clearly examine intracellular signaling pathways, allowing genetic manipulation of those pathways to change their function and better understand how insulin and glucagon secretion are altered with that manipulation. They determined that activation of Gi protein signaling reduced insulin and glucagon secretion while activation of Gq protein signaling stimulated glucagon secretion but had both stimulatory and inhibitory effects on insulin secretion.

In addition, this approach allowed the scientists to introduce biosensors into the islet cells to measure intercellular signaling events within the cells and better understand how those are linked to hormone secretion.

Another advance was the combination of the pseudoislet system with a unique microfluidic device, developed by co-authors Matthew Ishahak and Ashutosh Agarwal, Ph.D., from the University of Miami, that allowed the investigators to simultaneously document the changes in both calcium ions and hormone secretion.

“The exciting thing about this approach is that we both deconstruct the islet for our manipulation and reconstruct it to understand functional consequences at a larger level,” Walker said. “Since we put the islet cells back together, we can look at both insulin and glucagon secretion, but in a coordinated manner. Both of the secretion profiles measured are reflective of intra-islet interactions that are happening as well.”

This work greatly benefited from the research environment and infrastructure at Vanderbilt, particularly the National Institutes of Health (NIH)-funded Diabetes Research and Training Center (DRTC) and the Vanderbilt Cell Imaging Shared Resource.

“Another research direction will be creating pseudoislets that replicate a specific disease state, such as pseudo-islets that look like native islets from an individual with type 1 diabetes,” Haliyur said.

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Scientists ‘re-train’ immune system to prevent attack of healthy cells

The body’s immune system can be re-wired to prevent it from recognizing its own proteins which, when attacked by the body, can cause autoimmune diseases like multiple sclerosis, a significant new study by UK scientists has found.

Autoimmune diseases are caused when the immune system loses its normal focus on fighting infections or disease within and instead begins to attack otherwise healthy cells within the body. In the case of multiple sclerosis (MS), the body attacks proteins in myelin—the fatty insulation-like tissue wrapped around nerves—which causes the nerves to lose control over muscles.

Led by a multi-disciplinary team from the University of Birmingham, scientists examined the intricate mechanisms of the T-cells (or white blood cells) that control the body’s immune system and found that the cells could be ‘re-trained’ to stop them attacking the body’s own cells. In the case of multiple sclerosis, this would prevent the body from attacking the Myelin Basic Protein (MBP) by reprogramming the immune system to recognize the protein as part of itself.

Supported by the Medical Research Council, the two-part study, published today in Cell Reports, was a collaboration between two research groups led by Professor David Wraith from the Institute of Immunology and Immunotherapy and Professor Peter Cockerill from the Institute of Cancer and Genomic Sciences.

The first stage, led by Professor Wraith showed that the immune system can be tricked into recognizing MBP by presenting it with repeated doses of a highly soluble fragment of the protein that the white blood cells respond to. By repeatedly injecting the same fragment of MBP, the process whereby the immune system learns to distinguish between the body’s own proteins and those that are foreign can be mimicked. The process, which is a similar type of immunotherapy to that previously used to desensitize people against allergies, showed that the white blood cells that recognize MBP switched from attacking the proteins to actually protecting the body.

The second stage, saw gene regulation specialists led by Professor Peter Cockerill probe deep within the white blood cells that react to MBP to show how genes are rewired in response to this form of immunotherapy to fundamentally re-program the immune system. The repeated exposure to the same protein fragment triggered a response that turns on genes that silence the immune system instead of activating it. These cells then had a memory of this exposure to MBP embedded in the genes to stop them setting off an immune response. When T cells are made tolerant, other genes which function to activate the immune system remain silent.

Professor David Wraith said: “These findings have important implications for the many patients suffering from autoimmune conditions that are currently difficult to treat.”

Professor Peter Cockerill, said: “This study has led us to finally understand the underlying basis of immunotherapies which desensitize the immune system”

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A new plant-based system for the mass production of allergens for immunotherapy

Allergies can significantly affect health and quality of life. While allergen immunotherapy provides long-lasting therapeutic relief to people suffering from environmental allergies, the therapy can last several years and requires large amounts of allergen. Now, researchers from the University of Tsukuba developed a novel system that enables the mass production of the major birch pollen allergen Bet v 1 in plant leaves in just a matter of days. In a new study published in Frontiers in Plant Science, they showed that their system not only produces large amounts of Bet v 1, but the purified protein was also highly reactive towards the IgE antibodies in sera from individuals with birch pollen allergy.

“The idea of allergen immunotherapy is to desensitize the body’s response to the allergen by exposing patients to it in gradually increasing amounts,” says corresponding author of the study Professor Kenji Miura. “Because a significant drawback is the difficult, expensive and low-yield production of allergens, our goal was to develop a new system that allows for the rapid and massive production of allergens that can be used in the clinical setting.”

To achieve their goal, the researchers turned to their previously established “Tsukuba system,” which makes use of a method called agroinfiltration. They first introduced the gene for Bet v 1 into a specific type of bacteria called Agrobacterium tumefaciens and let them grow. They then immersed leaves of the plant Nicotiana benthamiana into the bacterial solution to bring the bacteria into close contact with the plant, so the bacteria could transfer the Bet v 1 gene to plant cells, which in turn started producing the protein. To test the quality of their product, the researchers also produced the protein in Brevibacillus brevis, which is a standard bacterial host for protein production.

“We were able to purify 1.2mg of Bet v 1 protein from 1g leaves in just 5 days,” explains Professor Miura. “This is a relatively large amount that is otherwise difficult to achieve using standard methods. Our next goal was to test whether our protein was immunogenic, which is a prerequisite for immunotherapy.”

The researchers isolated sera from individuals with birch pollen allergy and mixed them with Bet v 1 protein purified from plants and bacteria. In both cases, the researchers were able to show that Bet v 1-specific IgE from the patients’ sera, which is the antibody causing the allergy, was strongly reactive to their proteins.

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