Suppression of Chronic Active Lesion Expansion as a Therapeutic Target in Multiple Sclerosis

Multiple sclerosis (MS) is a disease in which the immune system attacks the protective myelin coating around nerve fibres in the brain and spinal cord, leading to the formation of lesions. These lesions can disrupt nerve signalling and cause symptoms such as weakness, visual problems, and difficulties with balance and thinking.

When a lesion first forms, it is driven by acute inflammation, a short-lasting but intense immune attack that rapidly damages myelin. After this phase, the centre of the lesion becomes a chronic scar, where most active inflammation has settled but the tissue is permanently injured. Importantly, in many people with MS there is a third process: a thin rim of ongoing, low-grade inflammation at the edge of old lesions. This “edge” or “smouldering” inflammation can persist for many years and slowly damage surrounding nerve fibres, causing lesions to gradually enlarge and contributing to long-term disability and brain shrinkage.

We believe that this edge inflammation reflects failure of the brain’s natural repair process, known as remyelination, in which damaged nerve fibres are re-covered with new myelin. When remyelination is successful, inflammation at the lesion border is dampened and the lesion stabilises. When repair is incomplete, immune cells remain active at the edge, maintaining smouldering inflammation and driving slow outward growth of the lesion.

The aim of this project is to determine whether therapies designed to promote remyelination can reduce this chronic edge inflammation and prevent long-term lesion expansion. We will analyse MRI and clinical data from completed clinical trials of remyelinating treatments to identify imaging signs of edge activity and to test whether these treatments are associated with stabilisation of lesion borders.

By developing reliable imaging markers of smouldering lesion activity and treatment response, this research aims to provide new tools for evaluating therapies that target the progressive, slow-burning damage in MS, ultimately helping to improve long-term outcomes for people living with the disease.