Multiple sclerosis, hitting the right target to protect gray matter

Multiple sclerosis, hitting the right target to protect gray matter

Study the mechanism of action of drugs already used in the treatment of multiple sclerosis to understand how to enhance treatment against the progressive forms, the most difficult to treat. It is with this objective in mind that a group of researchers spread across the universities of Toronto, Basel and Mainz embarked on a detailed study of the action of drugs that target the CD-20 protein expressed on B lymphocytes. The results of the their work was featured on the pages of Science Translational Medicine.

Although this is a preliminary study, mostly conducted on animal models and samples from patients, the research suggests some strategies to enhance the action of anti-CD20, which point straight in the direction of a protein with neuroprotective action: BAFF. But let’s go in order.

Learn more about the mechanisms of action

There are drugs that target CD-20 that work against multiple sclerosis – ocrelizumab is one of these – and are able to counteract the formation of new lesions in the central nervous system, reducing disability. However, some forms of the disease are more difficult to treat than others, and for these there is a desperate need for new therapeutic solutions. This is the case of progressive forms of the disease.

Ocrelizumab, in particular, works quite well in relapsing-remitting forms, less so in progressive ones, Valeria Ramaglia, associate researcher at the Department of Immunology at the University of Toronto, one of the authors of the paper, tells Salute. “B lymphocytes, targeted by anti-CD20, accumulate in the meninges of patients from the beginning of the disease and are associated with damage to the cerebral cortex as the pathology evolves. Ocrelizumab reduces lesions in the central nervous system and progression of disability, but we don’t know exactly how it exerts its benefits.”

There are two hypotheses in this regard, continues the Italian researcher: the first is that by eliminating B lymphocytes, the pathological processes induced by the lymphocytes themselves are eliminated, but it is also possible that by eliminating B lymphocytes, another protective mechanism is triggered. “We also wanted to understand if ocrelizumab, in addition to acting on the white matter (the nerve connections, ed.) could have some effect on the gray matter (the cell bodies of the neurons themselves, ed.)”, continues the researcher. Multiple sclerosis itself, in fact, is characterized by lesions affecting the white matter, but the progression of the disease also causes damage to the gray matter and loss of brain volume, the authors recall.

Promote neuroprotection

Experiments, observations from past clinical trials, and analyzes of human samples suggest that eliminating B cells triggers a neuroprotective effect. Scientists have in fact observed that, when some animal models of the disease were treated with anti-CD-20, it was possible to observe benefits also at the level of the cerebral cortex and therefore of the gray matter. Benefits attributable to a protein known as BAFF, they hypothesized. “Studies on patients had shown that people treated with anti-CD20 had higher levels of this protein and that when BAFF is blocked the patients worsen – continues Ramaglia – we also know that when BAFF is very high in animal models of the disease this does not develops.” So when the researchers went to treat the mice with both anti-CD20 and anti-BAFF they found that the disease progressed, as if blocking BAFF blocked the benefits of ocrelizumab, they explain. “The neuroprotective action of this protein was also confirmed by the analysis of the plasma of some patients treated with ocrelizumab: when BAFF was higher, neurodegeneration was lower.”

The significance of the study and future developments

How to interpret all this information? For Ramaglia, having shed more light on the mechanism of action of anti-CD-20 is important especially for the progressive forms of multiple sclerosis. “We know that these drugs work, but we have clues that make us think that their action must be somehow ‘pushed’ into progressive forms, acting for example on BAFF. Perhaps in the future we could imagine developing therapies in combination with anti-CD20s to enhance their action”. And this is why the researchers’ next steps will aim to delve deeper into the neuroprotective mechanisms of BAFF.

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