Effectiveness of VBP15, a dissociative steroidal analogue, on chronic inflammation in a mouse model of multiple sclerosis - ¿
DESCRIPTION (provided by applicant): Glucocorticoids (GC's), such as prednisolone, are used frequently to induce remission and treat multiple sclerosis (MS). Despite effectiveness, many GC mediated detrimental side effects including osteoporosis and muscle atrophy limit long term chronic treatment of MS patients. These side effects are believed to be mediated by well described glucocorticoid response element (GRE) mediated transcriptional properties (transactivation), whereas efficacy is mediated by trans-repression of NFkB pro inflammatory pathways. ReveraGen BioPharma has identified a lead compound, VBP15, that is a novel dissociative steroid designed to maintain the anti-inflammatory efficacy of traditional steroids through NFkB inhibition and GR translocation, yet has lost GRE mediated transcriptional activities leading to much less side effects typically associated with traditional glucocorticoid drugs (no osteopenia, growth stunting, or steroid myopathy). Importantly, VBP15 has been shown to reduce inflammatory activity in vivo across multiple murine models of disease. Furthermore, we have demonstrated in a pilot study that VBP15 significantly reduces the severity of disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (preliminary data). Thus, VBP15 may represent a safer and more effective alternative to traditional glucocorticoids in the treatment of MS. The goal of this STTR research is to extend preclinical evaluation of VBP15 by assessing the effect of treatment on disease in the mouse chronic relapsing remitting EAE model using published recommendations for pre-clinical studies. We hypothesize that VBP15 treatment after disease onset will result in similar anti-inflammatory activity compared to prednisolone but possess a much reduced side effect profile. As VBP15 has already entered Phase 1 clinical trials in adult healthy volunteers, transition to MS trials would likely ensure shortly after the successful completion of the proposed STTR grant.
