Effect of VBP15, a dissociative steroidal analogue, on intestinal epithelial repair processes in inflammatory bowel disease

 描述(申请人提供)：糖皮质激素(如强的松龙)经常被开用于治疗炎症性肠病(IBD)。尽管有效，但据信由GRE介导的转录特性引起的不良副作用限制了IBD患者长期使用糖皮质激素。此外，这些GRE介导的转录活性先前已被证明与糖皮质激素诱导的肠上皮损伤愈合有关。这可能解释了为什么糖皮质激素在维持疾病缓解方面似乎并不有效。ReveraGen BioPharma已经发现了一种新的解离类固醇化合物(VBP15)，它保留了传统类固醇的抗炎功效(通过抑制NFkB)，但失去了GRE介导的转录活性。VBP15治疗已被证明在多种疾病模型中减少体内炎症活动，包括TNBS诱导的小鼠结肠炎模型(初步数据)，并导致更温和的副作用。此外，在利用上皮损伤诱导的葡聚糖硫酸钠结肠炎小鼠模型的初步研究中，与强的松龙相反，VBP15降低了疾病的严重性，这表明VBP15可能对受损肠上皮的修复过程具有更良性的影响。因此，在IBD的长期治疗中，VBP15可能是一种比传统糖皮质激素更有效、更安全的替代方案。这项STTR提案的目的是证明VBP15与传统的糖皮质激素不同，在体外和体内都不会损害受损肠上皮的修复。因此，鉴定一种抑制促炎活性并且不损害肠道上皮有效恢复的化合物可能是一种可能的治疗方法 改变炎症性肠病的自然病史。

 DESCRIPTION (provided by applicant): Glucocorticoids (e.g. prednisolone) are prescribed frequently to treat inflammatory bowel disease (IBD). Despite effectiveness, adverse side effects believed to be caused by GRE-mediated transcriptional properties limit long term use of glucocorticoids in IBD patients. Furthermore, these GRE-mediated transcriptional activities have been previously shown to be responsible for glucocorticoid-induced impaired healing of the intestinal epithelium. This may explain why glucocorticoids do not appear to be effective in maintaining remission of disease. ReveraGen BioPharma has identified a novel dissociative steroidal compound (VBP15) designed that retains the anti-inflammatory efficacy of traditional steroids (via NFkB inhibition), but has lost GRE-mediated transcriptional activities. VBP15 treatment has been shown to reduce inflammatory activity in vivo in multiple models of disease including the TNBS-induced mouse model of colitis (preliminary data) and result in a much milder side effect profile. Furthermore, in preliminary studies utilizing the epithelial injury- induced dextran sodium sulfate mouse model of colitis, VBP15, in contrary to prednisolone, reduced disease severity suggesting that VBP15 may possess a more benign effect on the restitution processes of the injured intestinal epithelium. Therefore, VBP15 may represent a more effective, yet safer alternative to traditional glucocorticoids in the long-term treatment of IBD. The goal of this STTR proposal is to demonstrate that VBP15, unlike conventional glucocorticoids, does not impair the restitution of injured intestinal epithelium both in vitro andin vivo. Thus, identification of a compound that inhibits pro-inflammatory activity and also does not impair efficient restitution of the intestinal epithelium may represent a therapeutic that possibly alters the natural history of inflammatory bowel disease.