Seeking Answers for Progressive MS

A meeting in Boston early in March drew more than 80 scientists and clinical researchers to address the vexing question of how to speed treatments for progressive MS. The meeting showcased a cross section of potential disease mechanisms, new animal and computer models, and the scientific underpinnings of clinical trials by drugmakers.

In most countries, a dozen drugs are now available for relapsing-remitting MS (RRMS), the most common form of MS. Yet, none of the disease-modifying therapies for RRMS has been proven to be effective in progressive MS, of which there are two types. In some people, MS begins as primary progressive disease (PPMS). And among people with RRMS, more than half eventually develop secondary progressive MS (SPMS).

“Developing treatments for progressive MS is probably the biggest challenge facing the MS world,” Alan Thompson, M.D., told 1800 people signed up for a postmeeting webcast. The one-hour archived presentation and transcript is available at the website of the U.S. National Multiple Sclerosis Society.  “People with progressive MS, primary and secondary, have been waiting for decades. I can’t emphasize how much things have changed, and how much progressive MS is at center stage,” said Thompson, a neurologist at University College London, who cautiously predicted that two or three new treatments may be available within the next 10 years.

The small gathering in Boston represented the second scientific meeting of the International Progressive MS Alliance, and MSDF was the only news organization invited to attend. The U.K.-based collaboration of MS charity organizations and other stakeholders first came together 3 years ago to make progressive MS a global research priority and to translate the research into effective treatments (Fox et al., 2012).

Over the next 5 years, the alliance will channel €22 million ($28.9 million U.S.) from the National MS Society into the progressive MS research agenda. Last fall, the alliance funded 22 short-term pilot studies. The alliance received more than 50 applications involving over 450 investigators for the next round of larger 4-year grants to fund collaborative networks, Thompson told MSDF.

Thompson chairs the alliance’s scientific steering committee and also serves on the Lancet Neurology editorial board. For the February 2015 issue of the journal, he organized a special set of articles on progressive MS. Three review papers covered recent progress in understanding pathological mechanisms (Mahad et al., 2015), treatment needs (Feinstein et al., 2015), and clinical trials (Ontaneda et al., 2015). Two accompanying commentaries emphasized the tangible value of the patient perspective for informing scientific and clinical research (Coetzee et al., 2015) and provided an update on the international effort to find solutions (Thompson, 2015).

A new focus

Outside the recent meeting in Boston, record-setting snowfall was snarling traffic and arctic winds swept ice out of the harbor. Inside, a cross section of researchers, clinicians, industry scientists, and MS patient advocates warmed themselves with a sense of purpose and enthusiastic discussions that spilled into session breaks and mealtimes.

“It brought tears to my heart to hear that [so many] smart people around the world care about my disease,” said Elissa (EJ) Levy at the opening dinner in Boston. “It makes it easier to get up every day.” Levy was diagnosed with SPMS in 2002. Five years later, Levy founded MS Hope for a Cure to earmark her fundraising for the National MS Society, now up to almost $7 million, specifically for progressive MS research. “I know that every single dollar is going to fund the best research that will make a difference,” she said.

On paper, meeting organizers spelled out three lofty goals: Clarify and challenge possible pathological mechanisms of progressive MS, identify druggable targets, and look to related fields for lessons and strategies. Attendance was limited to allow for more discussion and interaction. Chosen topics ranged from the familiar MS evidence base to new and provocative ideas from other fields. 

While the meeting may have raised more questions than it answered, it succeeded in clearly focusing the research community on progressive MS, defining future research needs, and revealing potential new ways to find solutions, meeting co-chair Robert Fox, M.D., of the Cleveland Clinic in Ohio told MSDF.

“The original goal was to get everyone to agree on the mechanisms driving disease,” Fox told MSDF after the meeting, but he and others did not think there’s enough data yet for such a consensus. “It’s hard to know what is a secondary downstream phenomenon and what is driving disease,” Fox said. “All observations may be correct. But many may be the result of a degenerating brain.”

Complex biology

A stick-figure image from Fox’s introductory and closing talks illustrated the central conundrum. In the slide, simple drawings represent two people who experience transverse myelitis, an episode of spinal cord inflammation that can be an early sign of MS. Patient A recovers, while patient B progresses to secondary progressive MS 15 years later.

Fundamental questions include: Why does patient A stay stable and patient B decline? When does the progressive disease begin? What drives the disease, and what is a consequence of the disease process? How does one even know a person has progressive disease?

The phenotype descriptions of the two main types of MS were revised in 2013, based in part on new biological markers for RRMS: MRI imaging and clinical relapse rates (Lublin, 2014). No such clear clinical, imaging, immunologic, or pathologic criteria define the transition from RRMS to SPMS or the start of PPMS.

“It’s not always an easy thing to say whether a patient has progressive MS or not,” Fox said. “It may depend on what the patient is doing to stress the spinal cord and brain.”

Fox cited an example of a man, age 27, who developed optic neuritis and after an MRI was diagnosed with stable RRMS. Five years later, he developed foot-slapping at the end of marathons. Now age 40, he can only run 3 or 4 miles, but is asymptomatic when he is not running. “What’s the diagnosis now? SPMS? When did it start?” added Fox to the list of questions.

Some people may develop progressive MS symptoms when they push their bodies to higher physical performance levels. In others, extra cognitive capacity and the brain’s ability to compensate may mask symptoms of worsening progressive MS.

In fact, the brain’s functional reserve may explain the dissociation between disability rating scores and the functional neuropathological damage, said neurologist Giancarlo Comi, M.D., of the Scientific Institute San Raffaele.

Conceptual shift

At the meeting, there were as many different ideas about pathological drivers as there were presentations, but there seemed to be consensus that understanding molecular mechanisms will be key to success.

“To be successful, we must first understand the forces that drive the disease,” said Comi, who recently won a lifetime achievement award for his MS research. “There are probably many forces working together. Second, we need to use this knowledge to design new interventional strategies, not only to prevent damage, but also—this is new—to understand the recovery mechanism. We have to understand the functional reserve and why it fails at a certain phase of the disease.”

Two other priorities for the alliance, Comi and others noted, were new clinical trial designs and outcome measures, as well as better management of progressive symptoms such as bladder dysfunction, and evidence-based rehabilitation strategies.

During the talks and discussion, progressive MS emerged as a conceptually distinct pathology that may have little correlation with clinical symptoms, especially in the earliest stages. It may have its origins in the infiltrative inflammatory lesions of RRMS, which can cut across axons, or it may begin even earlier. Complicating matters, a minority of progressive MS cases may have an extended inflammatory component that may respond to disease-modifying therapies developed for RRMS.

“You’d have to be in complete denial to say MS is not an inflammatory disease,” said Peter Stys, M.D., of the University of Calgary, Alberta, Canada. “To me the question is: Is MS a primary autoimmune disease?” The idea that underlying degeneration may drive the inflammatory component in most people is called the “inside-out” hypothesis (Stys et al., 2012). Stys presented unpublished data that the locus of the disease may begin at the myelin-axon interface, perhaps due to chronically overactivated myelin receptors that may “tickle” the immune symptoms that escalate into RRMS for many and remain PPMS for some.

More evidence for an early start of progressive disease comes from a surprising source: children. “We don’t usually think of pediatric MS as progressive, but what we see at the earliest presentation is thalamic atrophy, suggesting that part of the disease is happening as early as we can look,” said Amit Bar-Or, M.D., of McGill University in Montreal, Canada, who is a scientific advisory board member of the Accelerated Cure Project, the parent organization of MSDF. “The horse is out of the barn earlier than we think” (Quintana et al., 2014).

Disease mechanisms

In opening sessions of the meeting, researchers presented more than a half-dozen mechanisms that may drive progressive MS and may reveal new drug targets. Marco Prinz, M.D., of the University of Freiburg, Germany, shared lessons from mice studies on the role of microglia, long-lived innate immune cells of the brain and spinal cord, as disease-enhancing cells in neurodegeneration. Microglia are cousins of the short-lived monocytes in the blood that can invade the brain during RRMS.

Francesca Aloisi, Ph.D., of the Istituto Superiore di Sanità in Rome discussed evidence that meningeal inflammation at the surface of the brain may eventually reach down into the gray matter of the cortex in a process independent of white matter inflammation. Among other evidence, she cited a new MRI study of 41 people with RRMS and progressive MS (Mainero et al., 2015). Researchers at Massachusetts General Hospital in Boston and their colleagues reported that worsening disability correlates with the deepening extent of pathological changes in the cortex. Aloisi suggested that MS is a complication of meningeal inflammation caused by a misguided immunopathological response to the Epstein-Barr virus, a widespread infection that is associated with risk for MS.

Degeneration and plasticity

When it comes to repairing myelin to save axons and stop further neurodegeneration, Robert Miller, Ph.D., of George Washington University in Washington, D.C., recommended thinking more broadly than oligodendrocytes as a target and drug-screening model. The number of oligodendrocytes does not tightly correlate to the amount of myelin around axons in postmortem tissue samples of people without MS, he said.

“We spend a lot of time using oligodendrocyte precursors and their differentiation as a surrogate for developing drugs,” said Miller, who has shown that astrocytes are crucial for myelin regeneration in mice. MS researchers also need to think about speeding up the naturally slow myelination of humans and mice, he added, and must also consider how different regions of the brain may locally regulate remyelination.

Astrocytes, the most numerous cells in the brain, secrete growth factors needed by myelinating oligodendrocytes, but reactive astrocytes may promote inflammation and block oligodendrocytes from maturing. In findings that show the importance of timing, Samuel Ludwin, M.D., of the Montreal Neurological Institute and Queens University, Ontario, Canada, has identified a molecular target that can inhibit reactive astrocytes in chronic disease but makes animals worse when given in active inflammatory disease.

Peter Calabresi, M.D., of Johns Hopkins University has been collaborating with a lipid biologist who works in the setting of HIV and dementia in hopes that lessons from another disease process may generate a hypothesis to test in MS. Myelin is 80% lipid. “It’s early times, but there are interesting clues that lipid species may serve as biomarkers of progressive MS,” he said. Unfortunately for those seeking both a broad and deep understanding of progressive MS pathophysiology, lipid biology is confusing—“almost as bad as immunology,” he joked.

A newer area of progressive MS research involves the role of mitochondria, the cellular power plants, pointed out Don Mahad, M.D., Ph.D., of the University of Edinburgh, U.K. Mitochondria in neuronal cell bodies hunkered down in gray matter may be damaged just when more energy is needed by axons under duress. Mahad showed a comparative video of mice that could stave off motor fatigue and walk without falling off a rod after being given an unnamed protective experimental agent. A commercially available mitochondrial protective supplement, MitoQ, also rescued the phenotype if given early enough. “The timing is crucial,” said Mahad, who noted that some early interventions may require an exercise protocol in people as a more sensitive way to detect the repair of early-stage damage.

Computational strategies

A virtually untapped reservoir of potential drug targets in progressive MS is a mere tap of the keyboard away in public genomic data sets, said Cinthia Farina, Ph.D., of the San Raffaele Scientific Institute in Milan, Italy.

“When using high-throughput screening methods, the amount of interesting results which require further in-depth analysis is much larger than the amount of validation that we can perform in a single publication,” Farina told MSDF in a follow-up email. “This means that many of the results of genomics experiments become immediately available to the whole scientific community after publication of the first paper, and may help other scientists to build or validate new pathogenetic hypotheses, sparing time, experiments, resources.”

For example, Farina referred to ArrayExpress and GEO. “If you query GEO with the term Multiple Sclerosis, you can retrieve many genomics data sets relative to the disease,” she told MSDF. “Some refer to analyses of blood, others of cerebral tissue, others of cultured cells. Some of them are relative to progressive MS. These files contain raw data that we can elaborate with the help of bioinformatics professionals,” such as those in the session co-chaired by Farina.

So far, studies to tease apart genetic variants that may influence progressive disease are not large enough to generate significant results, the panelists agreed.

To overcome this issue, Andrea Califano, Ph.D., of Columbia University in New York City proposed tackling genomics data with systems biology tools, first to isolate the master regulators of disease-related gene expression, and then to identify candidate genetic loci influencing the activity of the master regulators, an approach that helped identify key genes to target in clinical trials for aggressive prostate cancer and breast cancer. Califano emphasized the importance of going back to the lab to validate the algorithm-driven discoveries.

Philip De Jager, M.D., Ph.D., of Brigham and Women’s Hospital in Boston suggested large-scale application of “-omics” approaches to human disorders. In his lab, De Jager, a member of the Scientific Advisory Board of the Accelerated Cure Project, and his colleagues have been integrating gene susceptibility with expression data for drug discovery in Alzheimer disease, generating a pipeline of compounds that may translate to MS.

The bioinformatics approach has limitations, De Jager pointed out. The field is evolving rapidly. Methods are changing. Data are changing. Platforms are imperfect. And of course data sets are only as good as the study designs behind them.

Sergio Baranzini, Ph.D., of the University of California, San Francisco (UCSF), has developed a bioinformatics tool that integrates various types of information, including genetic susceptibility variants, protein-protein networks, and drug-gene interactions. “We can put together public databases into master networks,” he said. Such data integration can be queried to identify and prioritize drugs targeting pathogenic processes.

“The morning talks remind us how difficult MS is and how little we know about the [disease] mechanisms,” Baranzini said. “The afternoon has been more adventurous. Honestly, I think new approaches and ideas are needed in the field. Some may be wrong.”

New models

Pinch-hitting for a speaker who was unable to attend, Bruce Trapp, Ph.D., of the Cleveland Clinic in Ohio presented data on a potential animal model for progressive MS, a clear need in the field. The work was funded by the first round of pilot grants awarded by the alliance last fall.

Trapp calls it the “triple hit” model. Three cycles of demyelination in the cuprizone mouse overcome the famed ability of the brain to remyelinate, and the mice begin to show symptoms resembling the irreversible and continuous neurological decline of progressive MS in people, including measures of brain atrophy. Behavior readouts in an elaborate rectangular box called a neural cube showed encouraging behavior changes that could be quantitatively measured for drug testing.

In other model systems, Gianvito Martino, M.D., of the San Raffaele Scientific Institute in Milan, Italy, discussed how stem cells derived from patient skin samples can be reprogrammed into stem-cell-like precursor cells and then coaxed to differentiate into mixed neurons, astrocytes, and oligodendrocytes to create a reliable “disease in a dish” as a neuroprotective screening platform.

Luke Lairson, Ph.D., of the California Institute for Biomedical Research in San Diego gave an update of his lab’s search for agents that stimulate remyelination (Deshmukh et al., 2013). The strong early drug candidates, benztropine and clemastine, which was also identified independently in the lab of Jonah Chan, Ph.D., of UCSF (Mei et al., 2014), may have side effects too potent to make them good therapeutics, but another antimuscarinic agent his lab is developing may work better and at an earlier stage. Remyelination agents will also need to be given in combination with immune-modulating drugs developed for RRMS, Lairson and others said.

Taking a more direct approach, Norbert Goebels, M.D., of the University of Düsseldorf, Germany, has trained a time-lapse microscope on slices of mouse brain to look at the effect of inflammation on myelin and to study ongoing myelination. Using this “Burger King approach,” he has established two experimental paradigms that may replace some experimental autoimmune encephalomyelitis (EAE) mouse models for testing.

Into the clinic

Models are ultimately a poor substitute for human disease, noted David Baker, Ph.D., of Queen Mary, University of London. “We’ve let animal models dictate in the clinic. We may be missing a lot with our tools. We need to start with humans and reverse-translate into animals.”

Baker also recommended learning from mistakes. Over 2000 drugs treat EAE, while only eight classes of drugs are approved for RRMS, he said. Animal studies need to be as rigorous as human clinical trials, including physiologically relevant doses, blinded control groups, and replicated results in different mouse models.

“We probably have more targets than we can cope with at the moment,” Baker said. “How can we tell which are more important?” A human study of a drug for SPMS will take 2 years to recruit, 2 years to conduct, and 2 years to analyze the data. “That’s a long time if it doesn’t work.” Better animal studies may help weed out the drugs destined to fail.

The meeting’s final marathon session showcased drugs currently in progressive MS clinical trials and the scientific rationale for them. Pharmaceutical companies Novartis, Genzyme, Teva, Opexa, Hoffmann-LaRoche, and Biogen all have drugs in progressive MS trials. “Many of these trials will teach us a lot about progressive MS,” Fox said, “just as we learned a lot in tests of anti-inflammatory therapies.”

Key open questions

• What are the best strategies for encouraging productive research in progressive MS and for funding that research?
• What are the mechanisms driving progressive disease?
• Why does one person with MS stay stable while another declines?
• What’s the best way to determine when an individual starts down the pathway of progressive disease?
• What is the source of “functional reserve,” and why does it fail at some point in the disease?
• What can pediatric MS teach us about progressive MS?
• What is the role of meningeal inflammation and its interaction with EBV?
• Is it possible to speed up myelin regeneration? Is inhibiting reactive astrocytes the key?
• What’s the role of mitochondria in preserving distressed axons?
• What’s the best way to tame voluminous amounts of genomic data?
• What are the best strategies for preclinical testing of potential drugs for progressive MS?
• Which progressive MS drugs will perform best in clinical trials?