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MS Experts Gather to Review New Research Directions in Progressive MS

March 16, 2016

The first stand-alone meeting of the Americas Committee for Treatment and Research in MS (ACTRIMS) focused on progressive MS: what is currently known about the cause, and new research directions aimed at finding solutions for people living with progressive forms of the disease. The meeting, held in late February in New Orleans, had a strong emphasis on giving younger investigators opportunities to present their research. The National MS Society provided travel support to several of its funded postdoctoral research fellows as part of its strategic commitment to expand and increase the sustainability of the scientific workforce focused on MS.
Below are a few highlights of the meeting, including links to the presentations. For complete, free access to presentation summaries (abstracts), slide presentations and posters, browse the ACTRIMS 2016 Website.
Therapies Aimed at Stopping MS
In the Kenneth P. Johnson Memorial Lecture & Keynote address, Dr. Wolinsky noted progress in understanding progressive MS and lingering questions about what drives progression and how to treat and prevent it. He compared positive results of the recent trial of ocrelizumab in primary progressive MS to an earlier trial of a similar compound, rituximab, in primary progressive MS (OLYMPUS trial), which was not considered successful. One difference was that on average the people enrolled in the ocrelizumab study tended to be younger, had shorter disease durations, and had more evidence of active disease. One important need is that although progress has been made in characterizing different forms of MS (read more about types of MS), the MS research community still needs better ways of predicting early how an individual’s MS will proceed, and determining the best treatment course for that individual.
Available Therapies Slow Progression: A talk by Dr. Nathaniel Lizak (Monash University) won an award for best oral presentation by a young investigator. He described a study using MSBase, a large observational database that tracks clinical experiences and treatment histories of people with MS from 28 different countries. His team asked the question: how predictable is the progression of disability after individuals begin to experience moderate disability? They reported substantial variability, but that higher relapse rates increased later disease progression, and that the longer time a person was on one of the newer, stronger MS therapies, the less likely they were to progress to more advanced MS.
More Ocrelizumab Results: Dr. Jerry Wolinsky (University of Texas Health Science Center at Houston)  presented additional data from the completed trial of ocrelizumab in primary progressive MS. Previously announced results suggested that ocrelizumab significantly reduced the risk of progression of clinical disability by 24%, and showed other potential benefits. In additional analyses, they compared outcomes between participants who had active (“enhancing”) MRI brain lesions at the start of the trial to get an idea of whether people with active inflammation had more benefit. Although the trial was not designed to explore this difference, they found that a proportion of participants both with and without active lesions showed treatment benefit. In terms of safety, the most common adverse event was infusion-related reactions, and a higher proportion of those treated with ocrelizumab reported upper respiratory tract and oral herpes infections compared with those on placebo.
Addressing Inflammation: Dr. Peter Calabresi (Johns Hopkins University) described a clinical trial underway which attempts to stop inflammation of the tissue layer that surrounds the brain, called the meninges. This type of inflammation, often accompanied by clusters of immune cells, especially B cells, has been associated with nervous system damage in progressive MS and to a lesser extent, relapsing MS. The team’s phase 1 clinical trial of rituximab, given directly into the spinal fluid (intrathecally), is supported by the International Progressive MS Alliance. He noted that the team is still recruiting people with primary progressive or secondary progressive MS, and that so far 5 individuals had been treated, and they have not encountered serious adverse events.   
Stem Cells and MS: Dr. Andrew Goodman (University of Rochester) summarized discussion that occurred at an international conference on cell therapy co-sponsored by the National MS Society and ECTRIMS, held in late 2015 in Lisbon, and the different goals of various types of stem cell strategies under investigation in MS (read more). He noted that there are questions about how stem cell therapy may compare to other available therapies in terms of effectiveness and benefits, and that there is momentum toward the idea of a clinical trial in the future that would compare stem cell transplantation with a highly active immune-modulating MS therapy.    
Paths to Wellness
Interest in Diet and MS: Drs. J. Nicholas Brenton, Myla Goldman and colleagues (University of Virginia) mailed a survey to over 600 people asking about interest in changing diets to help address their MS. About one-third responded. The dietary approaches most favored by respondents were the paleo diet, high carbohydrate diet, low salt diet, and modified Atkins (low carbohydrate) diet. (Download a review of diet and MS.) The researchers concluded that there was sufficient interest to be able to recruit participants for a possible future clinical trial of modifying diet as a complementary approach to managing MS.
Treadmill and Cognition: Dr. Brian M. Sandroff (Kessler Foundation) and colleagues are seeking to determine if treadmill walking could improve cognitive function in people with MS. In a preliminary study they found that any intensity of treadmill walking (light, moderate, or vigorous) might improve an aspect of cognition called “inhibitory control” – the ability to bypass automatic responses. The team also reported that even in heat-sensitive people, rises in core body temperature during the walking did not nullify the benefits. The next step is to use these results to design and conduct controlled trials that will help determine longer-term benefits of walking on cognitive abilities in people with MS.
Mindfulness: Drs. Chloe Slowikowski (Carleton University), Ola Mioduszewski (University of Ottawa) and team recruited 47 people with all types of MS to complete questionnaires related to quality of life and "mindfulness." Mindfulness emphasizes improving awareness and acceptance of moment-to-moment experiences, including physical discomfort and difficult emotions. They reported links between higher levels of mindfulness and lower levels of depression, anxiety, fatigue and perceived cognitive deficits, and health-related quality of life. All of those who participated indicated willingness to participate in trial of a mindfulness training program which includes exercises such as meditation and yoga.
Understanding MS Progression
In an invited lecture, Dr. Claudia Lucchinetti (Mayo Clinic) described complex events that likely contribute to MS progression based on extensive evaluations of postmortem tissues and MRI studies. She noted that about 40% of MS brain lesions, or areas of damage, show signs of natural myelin repair in people with all types of MS. In progressive MS, disease activity appears to involve chronic or “smoldering” inflammation, and byproducts of this activity leads to other damage. She noted that therapies for progressive MS will have to target both inflammation and nerve degeneration. 
Inflammation and Injury: Dr. Pavan Bhargava (Johns Hopkins University) discussed recent discoveries pointing to a possible damaging role of inflammation of the meninges, a layer of tissue that surrounds the brain, in MS. In studies with colleagues, he used powerful MRI to identify and track inflammation of the meninges in mice with the MS-like disease EAE. This approach could be used to screen therapies targeting this process and help understand why it occurs in MS. Dr. Bhargava will continue these studies with a new Career Transition Fellowship from the National MS Society.
Drs. Roberta Magliozzi (Imperial College London), Massimiliano Calabrese (University of Verona) and team also studied inflammation of the meninges in MS. They evaluated proteins found in the spinal fluid and advanced brain MRI scans to see whether they could identify substances that were indicators or biomarkers of damage to nerve cells and to progressive disability. They reported finding inflammatory messenger proteins suggestive of meningeal inflammation in people with the most severe damage. This research, funded by the International Progressive MS Alliance, could result in a way of predicting early in MS who might need aggressive therapy aimed at reducing the risk of progression.
Inflammation and Progressive MS: The approved immune-modulating therapies for relapsing MS haven’t benefited most people with progressive disease. To understand why, Dr. Mika Komori (National Institutes of Health) and colleagues compared markers of immune activity in the spinal fluid of people with relapsing versus progressive forms of MS. They found no major differences in the levels of immune T and B cells in the spinal fluid. However, they found increased markers of inflammation that suggested immune cells in progressive MS are stuck inside areas of the brain, spinal cord and the meninges, where most therapies would not reach them.
Energy crisis in nerve cells? Dr. Don Mahad (University of Edinburgh) described research suggesting that when the myelin coating on nerve fibers is injured in MS, the tiny power houses inside the nerves – mitochondria – may malfunction and become unable to produce the energy needed to keep nerve cells alive. “If we can understand how mitochondria are damaged in MS and the consequences of that damage for neurological function,” he said, it may be possible to develop therapies to protect nerve cells, axons and myelin-making cells from harm and help prevent progression. 
Update -- International Progressive MS Alliance: Timothy Coetzee, PhD (National MS Society) described recent activities of the International Progressive MS Alliance, a coalition of 14 MS societies around the world focused on expediting the development of therapies for progressive forms of MS. The Alliance recently awarded 11 one-year “planning grants” to teams that are building networks to focus on drug discovery and target validation, identifying fluid biomarkers and imaging to better track progression, and testing rehabilitation strategies. The 11 teams will compete for subsequent 4-year, large-scale awards. The Alliance has plans for future scientific meetings and workshops in focused areas, and will continue to develop an industry forum to engage other partners in this effort.
Nervous System Repair
Imaging MS Lesion Repair: As part of her National MS Society-supported postdoctoral fellowship, Dr. Martina Absinta (National Institutes of Health) and colleagues have been using powerful MRI (7T) to track the evolution of MS brain lesions (focused spots of disease activity or damage). She reported that lesions that have undergone natural repair lose their distinct edge, or rim, that surrounds them. The investigators found some lesions that have persistent rims, which appear to indicate tissue damage that was not repaired. They conclude that these rims may be an important way to detect natural repair and the impact of future repair therapies. 
Watching repair in action: A poster presentation by National MS Society postdoctoral fellow Jennifer Orthmann-Murphy, MD, PhD (Johns Hopkins School of Medicine) was among two winners of the “Best Posters” award. She and collaborators are developing a mouse model that enables them to observe myelin-making cells in action. The team uses time-lapse imaging to view myelin damage in mice, and reported that they could observe the loss of myelin-making cells called oligodendrocytes, and observe how new ones formed new myelin. “We can use this model to determine when to intervene and test new therapies targeting myelin repair,” she said.

About Multiple Sclerosis

Multiple sclerosis is an unpredictable, often disabling disease of the central nervous system. Symptoms range from numbness and tingling to blindness and paralysis, and there is currently no cure for MS. The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are leading to better understanding and moving us closer to a world free of MS. An estimated 1 million people live with MS in the United States. Most people with MS are diagnosed between the ages of 20 and 50, and it affects women three times more than men.


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