Presenters at the cutting-edge developments in MS session deliver the newest key findings of pivotal studies. At the session, we heard about a novel therapeutic involved in remyelination, pathways that inhibit remyelination, a genetic risk factor that may also target the cell functions in the central nervous system, and reduced adverse events with extended interval dosing of an approved disease-modifying therapy.
Read on for highlights from the #ACTRIMS2018 cutting edge developments in MS research session.
Nanocrystalline Gold as a novel therapeutic for remyelination in multiple sclerosis
Current therapies in MS are immunosuppressive—targeting both the good and bad immune cells to prevent additional damage of the myelin. While these therapies are beneficial in slowing down progression of MS, they do not restore the lost function by repairing myelin by myelin-producing cells called oligodendrocytes. Oligodendrocyte precursor cells (cells that are immature and have not developed in mature myelin producing cells; OPCs) are detected around the lesions, yet it has been a challenging task to promote OPCs to mature. Dr. Michael Hotchkin from Clene Nanomedicine presented a novel treatment for the maturation of OPCs into oligodendrocytes—with the goal of promoting remyelination and improving symptoms. The therapeutic? The team developed a novel preparation of crystalline gold (Au) nanoparticles (CNM-Au8). While the mechanism of action of this therapy is being explored, Dr. Hotchkin believes it may be through regulating energy levels. In two different animal models of MS, Hotchkin presented robust remyelination response following CNM-Au8 treatment. Furthermore, Hotchkin showed restored behavioural function following demyelination. Therefore, CNM-Au8 is a promising new therapeutic candidate for MS—hence a human phase II clinical trial will commence in 2018.
IFN-γ signaling is a novel pathway that regulates oligodendrocytes precursor cells maturation
Oligodendrocyte precursor cells are being studied extensively in MS due to their potential to mature and promote remyelination. In this talk, Leslie Kirby (Johns Hopkins School of Medicine in Baltimore Maryland) presents a novel mechanism involved in preventing OPCs from maturing into myelin-producing oligodendrocytes. The signaling pathway of interest? IFN-γ. IFN-γ is a protein involved in cell-to-cell signaling, its levels are increased during MS activity, and administration of IFN-γ is shown to aggravate clinical disease resulting in increased number of relapses. Using a variety of methods, Kirby presents IFN-γ signaling in OPCs results in the enrichment of MHC class I antigen (set of cell surface proteins essential to recognize foreign molecules). Furthermore, IFN-γ signaling in OPCs was shown to activate toxic T-cells that led to cell death and suppression of remyelination.
Potential genetic risk factor in MS may also drive astrocyte function in development of lesions
Variations in multiple genes are thought to contribute to MS risk. However, whether these genes also impact cell function in the central nervous system remains unknown. Dr. Gerald Ponath (Yale University, New Haven, Connecticut) presents on a genetic risk variant, called rs7665090-G, driving astrocyte function in MS. Using induced pluripotent stem cells (adult cells that are pushed back to their stem cell fate) differentiated to the astrocytic fate that have this risk variant, Ponath showed enhanced NF-kB signaling (pro-inflammatory pathway this is thrown out of balance in MS) which results in recruitment of lymphocytes and toxicity. The risk variant directly perturbs central nervous system (CNS) cell functions through astrocytes, suggesting an interplay between the peripheral immune system and the CNS.
Extended interval dosing of Tysabri is associated with reduced progressive multifocal leukoencephalopathy risk
Inflammatory T cells enter the central nervous system by attaching to the blood-brain barrier with “sticky molecules”, called alpha-4 integrins. Approved treatment, Natalizumab (aka Tysabri), blocks alpha-4 integrin and prevents T cells from entering the central nervous system, where they cause inflammation and damage to myelin. Tysabri has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML). PML is fatal viral disease that causes progressive damage or inflammation of the white matter of the brain and can result in disability or death. Dr. Lana Zhovtis Ryerson (NYU Langone Health, New York University, New York) examined if extended interval dosing (EID) of Tysabri could reduce the risk of PML. The recommended dosage for Tysabri is 300mg, intravenously, every four weeks which was considered standard dosing (SD) in Dr. Ryerson’s paradigm. EID was based on dosing intervals greater than 5 weeks and less than 12 weeks. Of note, only people with MS who had anti-JC virus antibody were included in the analysis. The presence of anti-JCV increases PML risk. 13,132 individuals on SD and 1988 on EID were analyzed for the risk of PML. Ryerson showed a significant reduction in PML risk in the EID group compared to SD group. As the efficacy of Tysabri was not collected in this group, the benefit-risk of EID treatment was not assessed.
These new findings are sure to make a splash in MS. Where do you think the future of cutting-edge development lies? Leave a comment below.