Ever since disease-modifying therapies emerged onto the scene in the mid-1990s, suppression of damaging inflammation and prevention of the entry of harmful immune cells into the central nervous system (CNS) has formed the backbone of MS treatment. In more recent years, the dialogue has shifted to the topic of remyelination – in other words, coercing the body’s innate repair system to rebuild the myelin damaged during MS. This topic continues to be an unmet need in MS and is receiving a lot of attention at this year’s ECTRIMS conference, where the leaders in remyelination research have converged to share their perspectives and latest findings on myelin repair.
Professor Klaus-Armin Nave, Director and Scientific Member at the Max Planck Institute of Experimental Medicine in Göttingen, Germany, opened the session titled “Remyelination: mechanisms and therapeutic approaches” with a detailed overview of the role of oligodendrocytes in myelin repair. Oligodendrocytes, which are best known for producing the insulating myelin sheath that engulfs nerve fibres, also play an important role on their own – independently of myelin – in making sure that nerve fibres are healthy and have the “fuel” they need to sustain their metabolism. Using cutting edge data from both animal and cell studies, Prof. Nave showed that oligodendrocytes injured by inflammation can no longer deliver metabolic support to nearby nerve fibres, leading to their destruction – one of the factors believed to contribute to the mounting disability seen in progressive MS. Prof. Nave’s presentation really set the stage for the conversation about remyelination that followed by highlighting the need to focus on targets like oligodendrocytes – one of the keys to tackling disability progression with future therapeutic approaches.
Professor Catherine Lubetzki (University Pierre and Marie Curie, Paris, France) spoke about some of the emerging targets for remyelination that are in the drug development pipeline. Exogenous repair strategies, in which cells are introduced into the body for the purpose of stimulating myelin production, are still in the early experimental phases but are starting to show some promise. In particular, induced pluripotent stem cells (IPSCs), which are produced by genetically reprogramming an adult cell (such as skin cells) into an embryonic-like stem cell that has the potential to mature into myelin-producing cells, have demonstrated the ability to repair demyelinated spinal cords in animals with MS-like disease.
On the other hand, a handful of endogenous repair strategies, which harness the body’s own innate repair mechanisms, are further along in their development. Electrical stimulation of nerve fibres, originally introduced to the field of MS by Prof. Lubetzki and her colleagues in the 1990s, is one area that could potentially have a transformative impact in the years to come; in fact, a clinical trial is in the works that will use transcorneal (via the eye) electrical stimulation in people with optic neuritis to determine if this technique can improve deficits in vision.
Drugs targeting the retinoic acid receptor (RXR) are likewise on the horizon; new studies are showing that activating a specific RXR, which is found on oligodendrocytes, can promote myelin repair in animals following experimental demyelination. In fact, an experimental RXR drug called IRX4204 was the focus of a presentation by Dr. Martin Sanders (Io Therapeutics), whose study in animals with demyelination showed that the drug significantly promoted myelin repair. Collectively, these positive preclinical results have culminated in a small clinical trial that will test the safety and effectiveness of the drug bexarotene (which targets RXR) in people with MS, which is scheduled to begin in 2017.
Findings from the phase 2 SYNERGY clinical trial reveal that sometimes positive results in preclinical studies can have unexpected outcomes when they move to clinical trials. Presented by Dr. Diego Cadavid (Biogen Idec), the aim of SYNERGY was to test the experimental remyelinating drug opicinumab (also known as anti-LINGO-1) in combination with Avonex (used to control inflammation) to determine if it could reduce disability and improve physical and/or cognitive function in people living with active relapsing-remitting or secondary progressive MS. The trial’s 418 participants were assigned to different treatment groups that received one of four different doses of opicinumab or an inactive treatment (placebo) every 4 weeks for up to 72 weeks. Unexpectedly, individuals in the placebo group performed better than expected, with 49% showing improvement in function; since improvements in the opicinumab treated group were only modestly higher, the trial failed to reach its primary endpoint. In those treated with a 10mg/kg dose of opicinumab, 63% showed improvement, 65% showed improvement at 30mg/kg, while only 40% (fewer than placebo) showed improvement at the highest dose of 100mg/kg. Dr. Cadavid and colleagues crunched the data further to see if separating the participant group by different characteristics could provide more information about the response to treatment. They found that patients who were generally younger and had experienced a shorter disease duration and had fewer lesions in the brain fared relatively better on the treatment.
On a final note, a study on remyelination conducted by endMS Doctoral Studentship awardee Samuel Jensen, under the supervision of Dr. V.W. Yong at University of Calgary, was featured at Friday’s poster session. A great deal of research supports the beneficial effects of physical activity on MS symptom management, and Mr. Jensen’s research proposes that physical activity can provide benefits, in part, by promoting myelin repair. Using mice in which experimental demyelination was stimulated in the spinal cord, Mr. Jensen tested whether animals given free access to a running wheel could experience myelin repair compared to those with a locked wheel and very little opportunity for exercise. He found that as early as several weeks later, both the number of myelin-forming oligodendrocytes and the number of nerve fibres coated with myelin were increased in the exercise group relative to the inactive one. These findings may account for some of the improvement in overall wellbeing experienced by people living with MS who are able to partake in physical activity.
Overall, the findings presented at ECTRIMS reveal an emerging role for remyelination-targeting drugs on the MS therapy stage, and the MS Society will be keeping a close eye on the targets and pathways that were highlighted in this session. In the meantime, stay turned for more updates from ECTRIMS and follow the #ECTRIMS2016 hashtag on Twitter.