Multiple Sclerosis

Posted on Multiple Sclerosis

A recent early-stage stem cell therapy trial has demonstrated promising results in treating progressive MS.

Tie One on for Multiple Sclerosis

An international team has shown that the injection of a type of stem cell into the brains of patients living with progressive multiple sclerosis (MS) is safe, well tolerated and has a long-lasting effect that appears to protect the brain from further damage.

The study, led by scientists at the University of Cambridge, University of Milan Bicocca and Hospital Casa Sollievo della Sofferenza (Italy), is a step towards developing an advanced cell therapy treatment for progressive MS.

Over 2 million people live with MS worldwide, and while treatments exist that can reduce the severity and frequency of relapses, two-thirds of MS patients still transition into a debilitating secondary progressive phase of disease within 25-30 years of diagnosis, where disability grows steadily worse.

In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord.

Key immune cells involved in this process are macrophages (literally ‘big eaters’), which ordinarily attack and rid the body of unwanted intruders. A type of macrophage known as a microglial cell is found throughout the brain and spinal cord. In progressive forms of MS, they attack the central nervous system (CNS), causing chronic inflammation and damage to nerve cells.

Recent advances have raised expectations that stem cell therapies might help ameliorate this damage. These involve the transplantation of stem cells, the body’s ‘master cells’, which can be programmed to develop into almost any cell type within the body.

Previous work from the Cambridge team has shown in mice that skin cells re-programmed into brain stem cells, and transplanted into the central nervous system, can help reduce inflammation and may be able to help repair damage caused by MS.

Now, in research published in the Cell Stem Cell, scientists have completed a first-in-man, early-stage clinical trial that involved injecting neural stem cells directly into the brains of 15 patients with secondary MS recruited from two hospitals in Italy. The trial was conducted by teams at the University of Cambridge, Milan Bicocca and the Hospitals Casa Sollievo della Sofferenza and S. Maria Terni  (IT) and Ente Ospedaliero Cantonale (Lugano, Switzerland) and the University of Colorado (USA).

The stem cells were derived from cells taken from brain tissue from a single, miscarried foetal donor. The Italian team had previously shown that it would be possible to produce a virtually limitless supply of these stem cells from a single donor – and in future it may be possible to derive these cells directly from the patient – helping to overcome practical problems associated with the use of allogeneic foetal tissue.

The team followed the patients over 12 months, during which time they observed no treatment-related deaths or serious adverse events. While some side-effects were observed, all were either temporary or reversible.

All the patients showed high levels of disability at the start of the trial – most required a wheelchair, for example – but during the 12 month follow up period none showed any increase in disability or a worsening of symptoms. None of the patients reported symptoms that suggested a relapse and nor did their cognitive function worsen significantly during the study. Overall, say the researchers, this points to a substantial stability of the disease, without signs of progression, though the high levels of disability at the start of the trial make this difficult to confirm.

The researchers assessed a subgroup of patients for changes in the volume of brain tissue associated with disease progression. They found that the larger the dose of injected stem cells, the smaller the reduction in this brain volume over time. They speculate that this may be because the stem cell transplant dampened inflammation.

The team also looked for signs that the stem cells were having a neuroprotective effect – protecting nerve cells from further damage. Their previous work showed how tweaking metabolism – how the body produces energy – can reprogram microglia from ‘bad’ to ‘good’. This new study looked at how the brain’s metabolism changes after the treatment. They measured changes in the fluid around the brain and in the blood over time and found certain signs linked to how the brain processes fatty acids. These signs were connected to how well the treatment works and how the disease develops. The higher the dose of stem cells, the greater the levels of fatty acids, which also persisted over the 12-month period.

Professor Stefano Pluchino from the University of Cambridge, who co-led the study, said: “We desperately need to develop new treatments for secondary progressive MS, and I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS.

“We recognise that our study has limitations – it was only a small study and there may have been confounding effects from the immunosuppressant drugs, for example – but the fact that our treatment was safe and that its effects lasted over the 12 months of the trial means that we can proceed to the next stage of clinical trials.”

Co-leader Professor Angelo Vescovi from the University of Milano-Bicocca said: “It has taken nearly three decades to translate the discovery of brain stem cells into this experimental therapeutic treatment This study will add to the increasing excitement in this field and pave the way to broader efficacy studies, soon to come.”

Caitlin Astbury, Research Communications Manager at the MS Society, says: “This is a really exciting study which builds on previous research funded by us. These results show that special stem cells injected into the brain were safe and well-tolerated by people with secondary progressive MS. They also suggest this treatment approach might even stabilise disability progression. We’ve known for some time that this method has the potential to help protect the brain from progression in MS.

“This was a very small, early-stage study and we need further clinical trials to find out if this treatment has a beneficial effect on the condition. But this is an encouraging step towards a new way of treating some people with MS.” 

Posted on Multiple Sclerosis

“Multiple sclerosis: Immune cell activation in the gut revealed.”

Tie One on for Multiple Sclerosis

LMU researchers have demonstrated that autoreactive T cells are activated in a specific region of the intestinal tract, and this activation is dependent on the microbiome.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. It is triggered by certain T cells that infiltrate the brain and spinal cord, attacking the insulating myelin sheath around axons. In recent years, researchers have found increasing evidence that the gut microbiome plays a significant role in activating these cells. However, the precise location and underlying mechanisms remained unclear. Using imaging techniques in a mouse model, a team led by Privatdozent Dr. Naoto Kawakami from the University of Munich Hospital has now successfully tracked the microbiome-dependent activation of these cells live for the first time.

The scientists conducted a study using two-photon imaging to observe how specific T cells move and become activated in real time. They used a sensor protein to track changes in cellular calcium concentration, which helped them understand the T cells’ activity. The researchers focused on encephalitogenic T cells, which can cause inflammation in the brain. These T cells target a protein in the myelin sheath around neurons and are involved in the development of multiple sclerosis.

Activation in the lamina propria

The researchers showed that the cells need to be activated in the gut-associated lymphoid tissue (GALT), located in the mucous membrane of the gut, specifically in the lamina propria, a connective tissue layer of the small intestine. However, this only occurred when the mice had a healthy intestinal microbiome. If the gut was microbe-free, activation did not happen. It is interesting to note that activation in the lamina propria appears to be a general mechanism. Even non-encephalitogenic T cells, which target other molecules in the body, showed activation depending on the microbiome. The scientists believe that the microbiome produces molecules that are recognized by the receptors in the T cells and triggers cell activation.

In encephalitogenic T cells, the activation turns on genes that cause them to differentiate into so-called Th17 cells, as the researchers successfully demonstrated. Through this differentiation, the cells develop the properties that enable them to migrate into the central nervous system and trigger inflammation. “Our results make an important contribution to better understanding the development of multiple sclerosis and potentially open up new therapy options in the long term,” says Kawakami.

Posted on Multiple Sclerosis

Great news for people with multiple sclerosis – the COVID-19 vaccine is not associated with an increased risk of relapse.

Researchers identified immune cells as a potential key factor for protection against MS disease

“People with multiple sclerosis (MS) are at higher risk of severe coronavirus infection. However, there has been concern about potential relapse after vaccination. A recent study discovered that people with MS may not face a greater risk of relapse after receiving the COVID-19 vaccine. This study was published in the online issue of Neurology®,

“People with MS face a higher risk of severe COVID infection due to their level of motor disability or exposure to treatments that suppress their immune systems,” said study author Xavier Moisset, MD, PhD, of Clermont Auvergne University in Clermont-Ferrand, France. “Some previous studies have shown relapses after vaccination, causing some people to skip the recommended booster doses. The good news is that our study found no increased risk of relapse after COVID-19 vaccination for nearly all participants.”

Researchers discovered a small increase in relapse risk after a booster dose for patients with high MS activity. This was particularly evident in individuals who experienced at least two relapses in the previous two years, especially those who were not taking any MS medications.

The study included 124,545 individuals with MS in France. They had been living with MS for an average of 14 years and were monitored for 45 days after receiving the vaccine. This period was chosen because potential vaccine-induced relapses typically occur within 28 days after vaccination.

During the study, 102,524 individuals, representing 82% of the participants, received at least one dose of a COVID-19 vaccine. Among them, 95% completed the full vaccination regimen by receiving a second dose, and 59% received an additional booster dose.

In the 45 days following vaccination, researchers examined relapses that required treatment with high-dose corticosteroids.

“After adjusting for other factors that could affect the likelihood of a relapse, such as the time of year and the effect of disease-modifying therapy, researchers found that COVID-19 vaccination did not increase the risk of severe relapse. These results remained consistent after each dose.”

To confirm the findings, researchers compared people who had relapses with those who did not. Once again, they found no increased risk of vaccine exposure. Instead, they identified a slight decrease in relapse risk following vaccination.

“Our findings are reassuring: these vaccines can be used without any worry about the risk of relapse,” Moisset said. “The absence of such a risk is encouraging for people with MS. They may receive booster shots when needed, especially if booster shots are to be repeated in the future.”

“Moisset emphasized extra caution when considering booster vaccinations for patients with high inflammatory activity. It’s important for these patients to first receive disease-modifying treatment. Undertreated individuals and those with highly active disease showed a slightly increased risk after receiving the third vaccine dose. The risk was highest when both factors were combined.”

Posted on Fatigue, Multiple Sclerosis

Engaging in physical activity may help to prevent fatigue in patients with multiple sclerosis.

Naturally occurring peptide may tackle the ‘root cause’ of obesity-related conditions

A study led by the University of Eastern Finland has discovered that patients with relapsing-remitting multiple sclerosis (RRMS) experience lower levels of fatigue when they are in better physical condition and engage in higher daily activity. The study also revealed that lower disability rates were linked to reduced fatigue. These findings were published in the esteemed journal Multiple Sclerosis and Related Disorders.

Fatigue is a prevalent symptom in multiple sclerosis (MS) patients, but evaluating its impact on patients’ daily lives can be difficult. The study aimed to explore the connection between fatigue in patients with relapsing-remitting MS (RRMS) and their physical activity levels measured by accelerometers, as well as their level of disability.

The study utilized various measurement methods, including an accelerometer to measure physical activity, two different meters (MFIS and FSS) to measure fatigue, and two methods (EDSS and MSFC) to assess disability. Additionally, the study involved various physical performance tests.

Patients with a disability level of 0–2.5, considered moderately low, had higher fatigue levels than healthy controls, but lower fatigue levels than patients with a higher disability level (EDSS 3-5.5). There was a significant relationship found between fatigue and disability, as well as between daily physical activity and fatigue. A lower disability level, better physical condition, and higher daily activity were predictive of lower fatigue levels.

Fatigue plays a significant role in MS and has a strong impact on, for example, patients’ ability to work and premature retirement. This is of great importance socially.

“The findings are interesting and support previous studies very well,” says Doctoral Researcher Marko Luostarinen of the University of Eastern Finland. “Patients with MS should find a suitable form of exercise, taking into account their disability, which maintains their functional capacity and reduces fatigue.”

“This study is unique because it was large and used modern methods. However, more detailed research into patients’ disability and actual physical activity levels is needed,” points out Luostarinen.

Posted on autoimmune conditions, Multiple Sclerosis

“An engineered probiotic has been developed to treat multiple sclerosis.”

Terri wears a tie to promote MS awareness
Terri wears a tie to promote MS awareness

Brigham researchers are developing a new method to target autoimmune reactions in the brain using designer bacteria, aiming to make treatments safer and more effective.

Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, have developed a probiotic to suppress autoimmunity in the brain. This occurs when the immune system attacks the cells of the central nervous system and is at the core of several diseases, including multiple sclerosis. In a new study, researchers demonstrated the treatment’s potential using preclinical models of these diseases. They found that the technique offers a more precise way to target brain inflammation with reduced negative side effects compared to standard therapies. T

“Engineered probiotics could revolutionize the way we treat chronic diseases,” said lead author Francisco Quintana, PhD, of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital. “When a drug is taken, its concentration in the bloodstream peaks after the initial dose, but then its levels go down. However, suppose we can use living microbes to produce medicine from within the body. In that case, they can keep producing the active compound as it’s needed, which is essential when we consider lifelong diseases that require constant treatment.”

Autoimmune diseases impact around 5-8% of the U.S. population. Despite being widespread, there are limited treatment options for most of these diseases. Diseases like MS that affect the brain are especially difficult to treat because many medications can’t effectively reach the brain due to the blood-brain barrier, which acts as a protective barrier between the brain and the circulatory system.

In their search for new treatments for autoimmune diseases, researchers focused on dendritic cells, a type of immune cell found in high numbers in the gastrointestinal tract and around the brain. While these cells regulate the immune system, their specific involvement in autoimmune diseases is not yet fully understood. Through their study of dendritic cells in the central nervous system of mice, the researchers identified a biochemical pathway that these cells use to inhibit other immune cells from attacking the body.

“The mechanism we discovered acts like a brake for the immune system,” explained Quintana. “In most people, it is activated. However, in individuals with autoimmune diseases, there are issues with this braking system, which means the body lacks a way to defend itself from its own immune system.”

The researchers discovered that this biochemical brake can be activated with lactate, a molecule involved in numerous metabolic processes. Then, they successfully genetically engineered probiotic bacteria to produce lactate.

“Probiotics are not new – we have all seen them sold as supplements and marketed as a way to promote health,” said Quintana. “Using synthetic biology to get probiotic bacteria to produce specific compounds relevant to diseases, we can enhance the benefits of probiotics to the maximum.” They tested their probiotic in mice with a disease closely resembling MS and found that, even though the bacteria live in the gut, they could reduce the disease’s effects in the brain. They did not find the bacteria in the bloodstream of the mice, suggesting that the observed effect resulted from biochemical signalling between cells in the gut and in the brain.

“We have discovered in recent years that the microorganisms in the gut have a significant impact on the central nervous system,” said Quintana. “We focused on multiple sclerosis in this study to see if we can use this effect to treat autoimmune diseases of the brain. The results indicate that we can.” Although the current study only looked at the effect of the probiotic in mice, the researchers are optimistic that the approach could be easily adapted for human use because the strain of bacteria used to create the probiotic has already been tested in humans. The researchers are also working to adjust their approach for autoimmune diseases that affect other parts of the body, especially gastrointestinal diseases like inflammatory bowel syndrome.

Quintana and his colleagues are collaborating with Mass General Brigham Ventures to establish a new company. Mass General Brigham is renowned for its leadership in research and innovation, which has led to the formation of numerous companies driving scientific advancement and economic growth locally and globally. These companies allow patients worldwide to benefit from the discoveries made at Mass General Brigham. Quintana stated, “Using living cells as a form of medicine within the body holds great potential for creating more personalized and precise therapies. If the microbes in the gut can impact brain inflammation, we believe we can harness their power for other applications.”