Repurposing AMPAkines for enhancing myelin regeneration in multiple sclerosis (360G-Wellcome-204488_Z_16_Z)

Multiple sclerosis (MS) affects around 2.5 million people worldwide, with 130,000 affected in the UK, with an estimated economic cost of near to £4 billion per year. Currently, there are no fully effective myelin regenerative treatments available. Myelin regeneration can occur spontaneously in demyelinating diseases such as MS, and is essential for functional recovery. However, it often fails, leading to axonal degeneration and sustained clinical disability. Thus, promoting myelin regeneration is an important therapeutic aim, to which no treatments exist. We have shown that glutamate signalling is essential for myelin regeneration (Gautier et al., Nature Communications 2015)2. In new preliminary data we have identified an AMPAkine, S18986, that significantly increases myelin regeneration after demyelinating injury in an in vivo model of remyelination (see Fig. 7). We now wish to extend our investigation to address whether other AMPAkines have the same effect and whether, in immune system mediated white matter damage, these drugs, alongside S18986, are effective and safe. The aim of this pathfinder award is to further validate this therapeutic strategy in vivo and provide clear proof of concept evidence for using AMPAkines to promote myelin regeneration in MS. We will use two in vivo models, each modelling different aspects of MS to attain our following key goals: - Verify if identified AMPAkines enhance remyelination in vivo - Determine whether AMPAkines are protective in immune system mediated myelin damage. This work will clearly identify whether repurposing AMPAkines in combination with immune modification drugs is a therapeutic strategy for MS. The results of the proof of concept experiments funded by this pathfinder award will be critical to determine whether treatment with AMPAkines is a potentially effective strategy for promoting remyelination. These results are an absolute requirement to secure future translational funding to further develop AMPAkines as an effective treatment of white matter disease and to enable us to seek patent protection which will be essential for commercialisation. The future impact of identifying effective treatment for myelin regeneration is immense. Potentially, affecting huge numbers of people worldwide suffering from range of white matter diseases in addition to MS, which currently have no effective treatment.