Meet the Belgian company that is developing small molecule therapeutics to promote remyelination.
At ‘Rewind Therapeutics’ (a start-up company based in Leuven, Belgium), we focus on the development of treatments for neurological diseases. Myelin is the ‘insulation’ that wraps around neurons, and in turn, helps neurons to work faster and more efficiently. It is also the target of autoimmune attacks in multiple sclerosis (MS), and any damage to myelin is the proximate cause of the symptoms of the disease.
Myelin is formed by glial cells in the brain called oligodendrocytes; oligodendrocytes and their precursors account for about 30% of all the cells in the brain. The brain has a significant capacity to repair myelin when it is damaged. Repair is accomplished by mobilising stem cells called oligodendrocyte precursor cells (OPCs), which can migrate to the location of the myelin damage and differentiate into oligodendrocytes.
Failure of repair is associated with disability in diseases such as MS. The progression of disability in MS (a separate process from the relapses and remission that are the hallmark of the early stages of the disease) is believed to be associated with the brains failure to repair myelin. Myelin repair is a tightly regulated process, with mechanisms that both promote and inhibit repair. By manipulating the inhibitory processes, we hope to ‘remove the brakes’ so the repair process works more efficiently.
Things we do not know
Historically, treatments for neurological diseases have focused on neurons. While neurons are undoubtedly important, they represent perhaps less than half the cells in the brain. What is emerging is the appreciation that cells in the brain other than neurons can be the target for drugs that treat brain disease.
These other cell types include oligodendrocytes (which is what we focus on), but also astrocytes and microglia. New companies are emerging that are focused on developing therapeutics that target these other cells. This includes companies that are developing small molecule therapeutics, a few companies that are making biologics (antibodies) as well as a couple of companies that are focused on cell-based therapies.
MS is the immediate focus of our therapeutic efforts. We know that the disease results from autoimmune attacks on myelin, and these periodic attacks cause the initial symptoms of the disease. Over time, MS is associated with a progressive disability, so that patients are ultimately confined to a wheelchair and have several other disabilities. It is believed that this progressive disability reflects the loss of myelin, and the loss of the normal capacity to repair myelin – enhancing that capacity is our goal.
Oligodendrocyte development from OPCs has been studied for many years. We know a lot of the details in cellular and molecular terms, but there are still many unknowns. However, we do have the ability to study oligodendrocytes and their interactions with neurons in experimental models. Some of these models come from rodents, and it is also possible to make oligodendrocytes (and neurons) from human induced pluripotent stem cells (we use both). The use of these models has enabled the field to identify new drug targets, and to test new therapeutics.
The availability of these models enabled compound screening, and several studies published in the last three to four years reported successful repurposing screens where existing drugs were shown to promote remyelination both in vitro and in vivo. Based on these studies, at least one compound (clemastine) was taken into a clinical trial, and the trial demonstrated a successful ‘proof of mechanism’. This was the demonstration of a repair effect on the optic nerve, using visual evoked potentials, which suggests that the compound promoted remyelination. So far, no one had demonstrated an effect on a therapeutic endpoint using a remyelination approach.
Although a lot of preclinical work has suggested that manipulation of remyelination targets can improve myelination in animal models, we do not yet know how these effects will translate into clinical effects. We are still trying to learn how to translate observations in animal models into an impact on clinical disease.
Promoting remyelination – a novel approach to treating neurodegeneration
The therapeutic goal in MS is to slow progression of the disability associated with the disease. Historically, it has been difficult to develop drugs that slow the progression of neurodegenerative diseases. Indeed, the success in doing this in the pharma industry is essentially zero. This is a challenging goal. However, promoting remyelination is a novel approach to treating neurodegeneration.
Myelin damage is associated with several neurological disease other than MS. There are other autoimmune diseases, such as neuromyelitis optica spectrum disorder, that are conceptually similar to MS but which lack approved therapies. Multiple system atrophy is a progressive neurodegenerative disease where the pathology may originate from alpha synuclein deposits in oligodendrocytes (unlike Parkinson’s disease, where the alpha synuclein deposits are in neurons).
In addition to this, there are several leukodystrophies that are characterised by myelin damage. In acute brain injuries (such as stroke and traumatic brain injury), there is clearly damage to myelin. In these other disease areas, it is not yet clear whether remyelination therapies will have a therapeutic effect, but there are many exciting therapeutic areas to explore.
Dr Ian J. Reynolds
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