Small Vesicles Involved in MS Seen to Be Affected by Gilenya, Suggesting Potential as Biomarker

Gilenya (fingolimod) influences the release and function of small membrane particles, called extracellular vesicles, that are involved in the development of multiple sclerosis — and these vesicles may serve a biomarker of treatment effectiveness in people with relapsing MS, researchers report.

Extracellular vesicles (EVs) may also work as biomarkers for other disease-modifying MS treatments, they suggested.

The study, “The First Dose of Fingolimod Affects Circulating Extracellular Vesicles in Multiple Sclerosis Patients,” was published in the International Journal of Molecular Sciences.

Extracellular vesicles are small membrane particles that contain different types of molecules, such as proteins, lipids, and genetic material like small noncoding RNAs (sncRNA), which can be exchanged between cells. EVs can be released by different types of cells, and they are usually found in plasma or other types of body fluids.

Since their discovery, EVs are thought to be involved in cell-to-cell communication and in immune response modulation.

EVs have also been associated with the development of several diseases, including MS. Indeed, previous studies reported that EV plasma levels of EVs increase during relapses and return to normal during remissions in relapsing-remitting MS (RRMS) patients. In other forms of MS characterized by a lack of disease activity and inflammation, such as secondary progressive MS (SPMS), the levels of EVs are similar to those found in healthy individuals.

Based on these findings, scientists believe that EV levels in the peripheral blood of MS patients could reflect the inflammatory status of their condition and might be considered as biomarkers to monitor disease progression.

However, the precise immune function of EVs in the course of MS and the effects of classic immunomodulatory therapies on EVs remains a mystery.

Researchers in Spain collected peripheral blood and isolated plasma EVs from MS patients treated with Gilenya — marketed by Novartis and the first oral treatment approved for relapsing MS by the U.S. Food and Administration (FDA) — to determine if EVs were affected by the treatment.

Their study enrolled 11 patients, all in clinical remission. Blood samples were collected and studied immediately before and five hours after the first dose of Gilenya. Changes in the levels and content of plasma EVs were recorded, and their immune regulatory function assessed — that is, their ability to activate circulating immune cells.

Five hours after a first Gilenya dose, plasma EV levels rose substantially and their composition changed dramatically — “this analysis showed that 277 sncRNAs were present exclusively at 0 h and 274 only at 5 h” the researchers wrote.

In addition, EVs isolated before patients received Gilenya showed an increased immune regulatory activity and, consequently, a greater ability to activate immune cells involved in inflammation, compared to EVs obtained five hours after treatment.

“Before fingolimod (FGM) treatment, lymphocytes [immune cells] circulate freely in the blood stream, maintaining a proinflammatory status that is characteristic of MS,” the team wrote. “After first dose intake of FGM, this scenario changes; lymphocytes are arrested in lymph nodes, conditioning a low inflammatory status and thus the EVs released change to a low regulatory profile according to the circulating microenvironment.”

Altogether, according to the team, these findings suggest that EVs seem to be affected by immunomodulatory therapies in the first hours after their administration, supporting their use as potential MS biomarkers for early treatment monitoring.

“Similar approaches could be applied to study the effect of other immunomodulatory drugs for MS. Future experiments analyzing EVs in patients treated with … other drugs will continue to improve our understanding of EVs and their role in MS disease,” the researchers concluded.