May 16, 2016
MS Society-funded research team develops and tests a new compound to promote myelin repair in mice
The human body activates a complex repair program in response to damage to myelin, the substance that coats and protects nerve fibres in the central nervous system (CNS). The repair program involves the generation of new myelin-producing cells called oligodendrocytes that apply new myelin to affected nerve fibres, a process known as remyelination. In multiple sclerosis, the remyelination process can break down. Over time, the imbalance towards myelin destruction in MS leads to neurodegeneration – nerve cell death – and disability in the affected individual.
Researchers believe that the failure to remyelinate is likely a multifaceted problem caused in part by factors that block oligodendrocyte development at the site of injury. Scientists from the University of Calgary, including endMS doctoral studentship recipient Samuel Jensen and led by MS-funded researcher Dr. V. Wee Yong, have extensively studied a family of molecules known as chondroitin sulfate proteoglycans (CSPGs), which have been demonstrated to interfere with oligodendrocyte growth. In MS, CSPGs accumulate in regions known as lesions, areas within the CNS that harbour significant myelin damage. These molecules are known to get in the way of oligodendrocyte growth when studied in cell culture and they can also impede remyelination in animals with an MS-like disease. Dr. Yong’s team took a combined approach to overcoming the CSPG barrier by testing compounds known to both promote oligodendrocyte growth and block CSPG production. Their findings were published in the journal Nature Communications.
The Study and Results
The researchers tested whether drugs known to improve or accelerate oligodendrocyte development, including benztropine, clemastine, quetiapine, clobetasol and miconazole, were able to overcome the negative effects of CSPGs on oligodendrocyte growth. Unfortunately, no matter the drug given, oligodendrocytes grown in cell culture remained stunted and immature when CSPGs were present. The results forced the team to reconsider their initial approach and instead explore a method to interrupt CSPG production. They opted instead to manufacture their own drug, fluorosamine, which worked by blocking CSPG production rather than boosting oligodendrocyte development directly.
In MS lesions, CSPGs are generated in large part by astrocytes, cells of the CNS that help form a scar when the brain or spinal cord is injured. Using fluorosamine, the researchers were able to reduce the production of CSPGs by astrocytes in culture conditions, in turn allowing oligodendrocytes grown in the same environment to have a more normal development cycle.
Having established the drug’s potential beneficial effects in cell culture, the researchers next tested fluorosamine on living tissue. As expected, the drug reduced CSPG levels in mice with chemically-induced myelin damage while accelerating oligodendrocyte growth and remyelination capacity in the injured area. Animals that received a dummy solution rather than the drug did not see any improvement.
In a final set of experiments, Dr. Yong and his team assessed fluorosamine’s ability to treat inflammatory demyelination. As the majority of MS therapeutics work by dampening different aspects of the immune system, the researchers assessed whether fluorosamine could influence immune cell behaviour. The drug was first tested in culture conditions, where it suppressed the growth of activated T cells, a type of white blood cell involved in the MS autoimmune attack. Moving next to mice with an MS-like disease, the team demonstrated how treatment with fluorosamine reduced the severity of clinical symptoms in the animals – measured as the degree of disability in the tail, fore- and hind-limbs – when the drug was given either as a prophylactic (at onset of symptoms) or as a therapeutic (to animals who were already experiencing significant disability).
The research team led by Dr. Wee Yong has developed a new drug, fluorosamine, to block the synthesis of harmful CSPGs by astrocytes. By preventing CSPG accumulation, the drug was able to restore normal oligodendrocyte growth in cell culture, accelerate remyelination in mice with myelin damage, and reduce clinical symptoms in animals with an MS-like disease. Although promising, these experiments were conducted in cell culture and in mice, not in humans living with MS. More work is required before the findings, and their potential therapeutic applications, are translated from laboratory to clinic.
The study also highlights the difficulties inherent to developing MS therapeutics. Drug approaches must not only suppress or alter an aggressive immune system and boost remyelination capacity, but must also overcome inhibitory molecules secreted as part of the healing process. As the authors discovered, multiple drugs known to promote oligodendrocyte growth have failed to overcome the CSPG barrier. This does not, however, make these drugs ineffective. Dr. Yong suggests that an approach that combines the best of both worlds – neutralizing the inhibitory environment while promoting oligodendrocyte development – holds the most promise.
Astrocytes are also far from the villains they appear to be. They are a necessary piece of the CNS healing process and, under the right conditions, release molecules that enhance oligodendrocytes maturation, based on research conducted by former MS Society-funded postdoctoral fellow (and currently funded principal investigator) Dr. Craig Moore. Designing ways to isolate and target only inhibitory factors, while leaving other beneficial astrocytic molecules untouched, is a challenge for the future.
Keough MB et al. (2016). An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination. Nature Communications. doi:10.1038/ncomms11312.