There are currently no approved therapies to slow down the accumulation of neurological disability that occurs independently of relapses in multiple sclerosis. International agencies are working to expedite the development of novel strategies capable of modifying disease progression, reducing persistent central nervous system inflammation, and preventing the degeneration of axons in people with progressive multiple sclerosis. Therefore, a key priority of the lab is to identify the fuels and drivers of disease progression to design new approaches for the development of next generation therapies that will benefit patients.

​

Smouldering disease and neurodegeneration

Multiple sclerosis is a lifelong chronic inflammatory condition of the central nervous system that is characterised by demyelination, axonal/neuronal degeneration, and persistent activation of microglia and astrocytes. Nearly 85% of multiple sclerosis patients present with a relapsing-remitting disease course, while the remaining ~15% present with a primary progressive disease course that is characterised by a continuous neurological deterioration in the absence of clinically defined relapses. Despite great successes in the development of disease-modifying therapies, as the disease evolves, most patients with relapsing-remitting multiple sclerosis will advance to a secondary progressive disease course 15–20 years from disease onset. This has created a gap in available treatment options that benefit patients with progressive multiple sclerosis, which is due to an incomplete understanding of the specific mechanisms that characterise progression. These degenerative mechanisms are distinct from those present in relapsing-remitting multiple sclerosis and are insufficiently targeted by the currently approved immunomodulatory compounds. 

In relapsing remitting multiple sclerosis, active lesions predominate and present with a diffuse perivascular and parenchymal T cell infiltration that is the substrate of clinical attacks. As the disease evolves, and patients advance to the progressive phase of the disease, there is a shift from a T cell mediated adaptive immune response towards innate immune activation. This is characterised by a persistent state of central nervous system inflammation that is driven by cells of the myeloid lineage, such as microglia. In progressive multiple sclerosis, myeloid cells are found in the normal appearing white matter, in subpial cortical lesions and, most importantly, in smouldering lesions. These are slowly expanding lesions that are characterised by a rim of activated myeloid cells and astrocytes. Here, the activation of myeloid cells and astrocytes correlates with increasing demyelination and axonal loss, which leads to worsening symptoms. These observations point to slowly expanding, myeloid and astrocyte-mediated smouldering neuroinflammation as the core feature from which progression starts and evolves in multiple sclerosis. Importantly, smouldering or low-grade inflammation is also a main feature of a variety of metabolic diseases, including obesity, diabetes, and cardiovascular diseases. It also participates to the initiation and progression of several disorders of the immune system, including rheumatoid arthritis, psoriatic arthritis, and allergic diseases and chronic diseases of the nervous system.

Therefore, understanding fuels and drivers that contribute to the destructive myeloid cell and astrocyte activation in the central nervous system holds great promise in identifying new targets to treat and/or delay disease progressions.