From Skin Care to Brain Care
Sytheon/Symbionyx researchers published a paper – “A novel fumarate, isosorbide di-(methyl fumarate) (IDMF), replicates astrocytes transcriptome responses to dimethyl fumarate (DMF) but specifically down-regulates genes linked to a reactive phenotype” in Biochemical & Biophysical Research Communication, 532(3):475-481, 2020; https://doi.org/10.1016/j.bbrc.2020.08.079.
Dimethyl fumarate (DMF), trade named Tecfidera with over $4B annual sales, is marketed by Biogen as a first-line therapy for the relapse-remitting multiple sclerosis (RRMS) subtype. DMF treatment, however, is limited in some RRMS patients due to adverse effects (e.g., gastrointestinal symptoms, flushing, and lymphopenia). This has increased focus on the development of new fumarates that may have similar efficacy to DMF but will be more tolerable for RRMS patients. Sytheon focused on RNA-seq to characterize transcriptional responses to DMF in cultured astrocytes. Effects of DMF were then compared to those of isosorbide di-(methyl fumarate) (IDMF), which is a novel fumarate not previously evaluated as an RRMS treatment.
Our findings show that both DMF and IDMF alter the expression of MS-associated genes involved in antioxidant defense (HMOX1), extracellular matrix (MMP9, TIMP3), and inflammatory cell chemotaxis (CCL2). However, IDMF had specific effects downregulating the expression of genes linked to the cell cycle and a reactive astrocyte phenotype (ICAM1). These findings provide the first study of genome-wide expression responses to DMF in astrocytes and thus help to define astrocyte-centered mechanisms that may contribute to the efficacy of DMF as an RRMS treatment.
In addition, our results show that IDMF partially replicates transcriptional effects of DMF but also uniquely suppresses a gene circuit linked to the cell cycle and proliferation. Our findings, therefore, support a rationale for further evaluation of IDMF as a novel RRMS treatment with enhanced potential for activity against reactive gliosis and MS lesion scar formation with better tolerability.
Defining the mechanism of IDMF, demonstrating its potential superiority over DMF, and having secured broad patent coverage, Sytheon stakes claim through its sister company, Symbionyx Pharmaceuticals Inc., to delve into relapse-remitting multiple sclerosis market through partnership.