epigenetics

Multiple sclerosis (MS) is characterized by changes in methylation — a type of chemical modification in the DNA that changes how genes are read — in immune cells called T-cells, according to a new study. The results also suggest that treatments for MS can help to normalize methylation…

Vitamin D can influence the immune system’s tolerance to certain proteins by changing how DNA is packaged in specific immune cells called dendritic cells, according to a new study. Its findings could have implications for treating diseases like multiple sclerosis (MS) that are characterized by the immune system attacking…

The enzyme TET1, which is progressively lost with age, is essential to activate genes needed to repair myelin — the sheath around nerve cells that is damaged in people with multiple sclerosis (MS) — a study in mice has found. The…

A cluster of immune-related genes located in the X chromosome are more active in the X chromosome inherited from the mother than in the one from the father, a new mouse study shows. These findings may help explain why women have higher rates of autoimmune diseases, such as multiple…

A link between fat molecules called ceramides and worsening disease in overweight and obese people with multiple sclerosis appears to exist, a study reports, with its findings suggesting that ceramides prompt the growth of immune cells called monocytes, which in turn spurs disease progression. These results also strengthen the likelihood that lifestyle factors, like diet and weight, can act as disease modifiers, its researchers said. High body mass index has been linked to the risk of developing MS, but for reasons that aren't clear. One idea is that weight-induced differences in lipids (fat molecules) in the blood, because they are involved in several cellular signaling processes, may affect MS and its course in people with higher BMIs. To test this hypothesis, a team led by researchers at the Advanced Science Research Center (ASRC) at The Graduate Center and at the Icahn School of Medicine at Mount Sinai analyzed 54 patients with relapsing-remitting MS (MS), ages 18 to 60, and with normal or high BMIs (27 people in each group). Participants were followed for two years. BMI is a measure of body fat based on height and weight. A normal BMI is defined as one between 18.5 and 24.9, while a person is considered overweight with a BMI of 25–29.9, and obese it is 30 or higher. Researchers took blood samples, and looked for differences between the groups in terms of both immune cells and blood lipid profiles. They then validated their findings in a separate group of 91 RRMS patients. Patients with high BMIs tended to have more monocytes than those with normal BMIs. Monocytes can travel through the blood to tissues where they develop into macrophages, immune cells with various functions that are best known for "eating" invading bacteria. Monocytes can also travel to the brain and damage nerve fibers. Overweight and obese patients also had significantly higher levels of ceramides compared with normal-weight patients, and the researchers wondered if a link might exist between the two. Through a set of experiments in cells, they discovered that ceramides cause epigenetic changes in monocytes; that is, they alter the way their genomes are "read," so they alter gene activity. Specifically, ceramide-treated cells showed a type of epigenetic change called methylation — which generally turns genes "off" — in genes that normally help prevent cells from dividing. Conceptually, these genetic changes serve to unleash monocytes, leading them to grow more (proliferate) than they otherwise might. The researchers also found more methylation on the genomes of monocytes from high-BMI patients than those from low-BMI patients, and they noted that the overweight or obese patients also tended to have greater disease activity, worse disability progression, and more brain lesions on MRI (magnetic resonance imaging) scans on follow-up. Finally, the researchers tested a mouse model of MS, giving one group of mice a standard diet and another a high-fat diet. Mice fed the high-fat diet were found to have greater disease severity, more brain lesions, and more monocytes, confirming the findings seen in MS patients. "This study gives us a much-needed view into the environmental influences that can affect and change the behavior of cells in an individual's body," Kamilah Castro, the study's first author, said in a press release. "Our findings suggest that increased levels of saturated fat as a result of dietary habits are one likely cause of the epigenetic changes that advance MS, which gives us a starting point for a potential intervention." According to the team, the findings support the concept of nutri-epigenomics: that is, the ability of food to alter the way the genetic information is interpreted by each cell, and suggest that "weight management and dietary intervention" might affect MS prognosis. One limitation was the study's small size, its researchers noted. "While we consider our results … very exciting and mechanistic, we acknowledge that the potential consideration of ceramide levels as biomarkers for disease progression in MS would require validation ... using larger cohorts with a longitudinal and/or cross-sectional design," they concluded. "It will also be important to evaluate the effectiveness of dietary intervention (with an emphasis on the reduction of specific classes of saturated fats), as potential modulator of plasma ceramide levels and possibly of disease course in MS patients."

Treating multiple sclerosis with Tecfidera induces specific genetic alterations that may reduce the levels of immune T-cells targeting the central nervous system, researchers report. Environmental stimuli may induce epigenetic changes in cells — meaning not alterations in the genes themselves, but changes in gene expression (the process by which information in a gene is synthesized to create a working product, like a protein). Epigenetic changes may induce MS development, as these alterations can cause T-cells to attack the central nervous system. One type of epigenetic change is DNA demethylation, the removal of methyl chemical groups, in which molecules involved in metabolism (such as fumarate) interact with enzymes known as DNA demethylases. This process in key for T-cell activation, function and memory, suggesting that it could be an immunomodulatory target. Fumaric acid esters were shown to be effective in MS clinical trials, leading to the approval of Tecfidera (by Biogen) for people with relapsing-remitting forms of the disease. However, their complete mechanism of action remains unclear. Aiming to address this gap, scientists at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York and the Icahn School of Medicine at Mount Sinai, recruited 98 MS patients, either previously untreated (47 people, mean age of 38.4), treated with Tecfidera (35 people, mean age of 42.3), or treated with glatiramer acetate (16 patients, mean age of 43.4) — marketed as Copaxone by Teva Pharmaceuticals, with generic forms by Sandoz (as Glatopa) and by Mylan. All patients had stable disease for at least three months, but disease duration was shortest in untreated patients — 40.4 months vs. 130 months in those given Tecfidera, and 100 months in patients using glatiramer acetate. Blood samples were collected from each participant to assess epigenetic changes in T-cells expressing the cell surface marker CD4. MS patients typically have an activated form of these cells in their blood and cerebrospinal fluid, the liquid surrounding the brain and spinal cord. Results revealed that, compared to the other two groups, treatment with Tecfidera was associated with a lower percentage of T-cells containing the CD3, CD4, and CD8 markers, as well as lower levels of subsets of T-cells expressing the CCR4 and CCR6 receptors, which are critical to T-cell migration to the gut, brain, and skin. Treatment with glatiramer acetate resulted in significantly milder alterations in T-cell percentages compared to no treatment. Researchers then found that FAEs induce excessive methylation — the addition of methyl groups — in T-cells containing CD4, compared to glatiramer acetate. Specifically, this overmethylation was observed in a micro-RNA — tiny RNA molecules than control gene expression — known as miR-21, key for the differentiation of a subset of T-cells called T helper-17 (Th17) cells and for CCR6 expression in MS mouse models. These Th17 cells are critical in tissue inflammation and destruction, and have been implicated in MS. The epigenetic effects of FAEs were subsequently validated by comparing pre- to post-treatment with Tecfidera in seven patients. In turn, in vitro (lab dish) experiments showed that FAEs act specifically on the activation of naïve T-cells — those able to respond to new pathogens to the immune system — containing the CD4 or the CD8 markers. Of note, patients with MS have shown increased miR-21 levels, particularly during acute relapses. As such, the team hypothesized that its hypermethylation by FAEs could contribute to remission and the prevention of relapses in this patient population. These results "suggest that the metabolic-epigenetic interplay in T-cells could be harnessed for therapeutic purposes," the researchers wrote, and that the immunomodulatory effect of FAEs in MS is due at least in part to the epigenetic regulation of T-cells. The researchers believe that their findings have a broader implication, beyond MS. "Our findings about therapeutically active metabolites have implications for the treatment of not only multiple sclerosis but also other autoimmune diseases, such as psoriasis and inflammatory bowel disease, which involve the same type of T-cells," Achilles Ntranos, the study’s lead author, said in a press release. "Understanding the epigenetic effect of metabolites on the immune system will help us develop several novel strategies for the treatment of autoimmune diseases, which could help patients and physicians achieve better clinical outcomes," Ntranos added. Patrizia Casaccia, the study’s senior author, concluded: "It may one day be possible to target and suppress production of the specific brain-homing T-cells that play a role in the development of MS."

Australian researchers from the University of Newcastle and the Hunter Medical Research Institute (HMRI) have received funding for two projects that will study unexplored areas in multiple sclerosis (MS). The projects, investigating the role of epigenetic differences in MS severity and treatment against MS-derived fatigue, received $211,000 AUD (about $151,300…

Oryzon Genomics will give updates on its leading investigational product ORY-2001, a brain-targeting epigenetic therapy now in a Phase 2 clinical trial recruiting multiple sclerosis patients, at a series of scientific conferences. According to a press release, these include two conferences in the United States, the 2018 BIO…

Inhibiting an enzyme responsible for turning genes on and off can reverse damage to the myelin sheath that protects nerve cells, improving limb function, a multiple sclerosis-related study in mice shows. The research, which involved mice with sciatic nerve damage rather than MS, was published in the journal Nature Medicine.

Oryzon Genomics has enrolled the first multiple sclerosis patient in its Phase 2a SATEEN clinical trial investigating the therapy ORY-2001. The Spanish company will also present new results from preclinical models of MS treated with ORY-2001 at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2018, set for Feb. 1-3 in San Diego. ORY-2001 is an epigenetic therapy, meaning it targets the expression and activity of genes. The drug inhibits two particular molecules, LSD1 and MAOB, and was previously shown to reduce cognitive impairment and neuroinflammation in preclinical models, including in a mouse model of MS — the experimental autoimmune encephalomyelitis (EAE) model. The therapy was also shown to have neuroprotective effects. During ACTRESS 2018, Oryzon's chief scientific officer, Tamara Maes, will present a poster, "ORY-2001 reduces inflammatory cell infiltration in the Theiler’s murine encephalomyelitis virus model and highlights the epigenetic axis in MS.” “In previous reports we showed that ORY-2001 reduces the clinical score, lymphocyte egress, immune cell infiltration and inflammation protecting the spinal cord from demyelination in a murine MS-EAE model,” Maes said in a press release. “Here we provide data on the efficacy of ORY-2001 in the Theiler’s murine encephalomyelitis virus model for multiple sclerosis." In a second poster, "ORY-2001 in multiple sclerosis: first clinical trial of a dual LSD-1/MAOB inhibitor,” Roger Bullock, Oryzon's chief medical officer, will detail the Phase 2a trial, SATEEN, testing ORY-2001 in patients with relapsing-remitting or secondary progressive MS over a 36-week period, followed by an open-label extension. “Our first patient enrolled in SATEEN signals a new landmark for the clinical development of this drug in different neurological indications,” said Bullock. “This is the first epigenetic approach in this disease, and we hope that it will contribute to enlarge and improve the therapeutic options for patients afflicted by MS."

Smoking changes a DNA-based mechanism that influences multiple sclerosis patients’ gene activity, a Swedish study confirms. Another finding was that MS appears to aggravate the harmful effects of smoking. The study dealt with DNA methylation, the process by which the body adds methyl groups to a DNA molecule. Methylation can change…

Spain’s Oryzon Genomics will offer new data on the preclinical efficacy of ORY-2001, an epigenetic modulator it is developing to treat  multiple sclerosis (MS). Its presentation is set for Oct. 26 at MSParis2017, the joint international meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis…

The absence of epigenetic factors in myelin-producing oligodendrocyte cells make sure that myelin production is switched off in the adult brain. Targeting these factors may be a way of triggering myelin regeneration in multiple sclerosis (MS), and a step toward personalized medicine for this disease, Dr. Patrizia Casaccia said in a talk…

The second annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), a forum for clinicians, researchers and other MS specialists to network and discuss the  latest advances in MS research and treatment is set for Feb. 23–25. This year’s meeting takes place at the Omni ChampionsGate resort hotel in Orlando, Florida. Multiple Sclerosis News…

Researchers from Oryzon will present efficacy data on the company’s oral epigenetic drug ORY-2001, a potential treatment for multiple sclerosis (MS), at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) congress taking place this week in London. The poster presentation, “LSD1 inhibition, a potential epigenetic therapeutic approach for the…