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

VBP15（一种解离类固醇类似物）对炎症性肠病肠上皮修复过程的影响

• 批准号: 8833074
• 负责人: Jesse Damsker
• 金额: $ 22.5万
• 依托单位: REVERAGEN BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833074
• 关键词: Adrenal Glands; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Benign; Biological Assay; Bromodeoxyuridine; Cells; Chronic; Colitis; Data; Disease; Disease model; Disease remission; Duchenne muscular dystrophy; Effectiveness; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Functional disorder; Funding; Glucocorticoids; Goals; Growth; Immunosuppression; Impaired wound healing; In Vitro; Individual; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Institution; Intestines; Label; Lead; Lung; Measures; Mediating; Modeling; Moods; Mus; Muscular Dystrophies; Natural History; Osteopenia; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Process; Property; Protocols documentation; Publishing; Recovery; Relapse; Research; Research Personnel; Severity of illness; Small Business Technology Transfer Research; Sodium Dextran Sulfate; Steroids; Therapeutic; Therapeutics for Rare and Neglected Diseases; Transactivation; airway epithelium; analog; design; in vivo; injured; intestinal epithelium; monolayer; mouse model; novel; prednisolone; programs; public health relevance; repaired; wound

 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.

 描述（由申请人提供）：糖皮质激素（例如泼尼松龙）经常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糖皮质激素在IBD患者中的长期使用。此外，这些GRE介导的转录活性先前已被证明是糖皮质激素诱导的肠上皮愈合受损的原因。这可以解释为什么糖皮质激素似乎不能有效地维持疾病的缓解。ReveraGen BioPharma发现了一种新型解离甾体化合物（VBP15），该化合物保留了传统甾体的抗炎功效（通过NFkB抑制），但失去了GRE介导的转录活性。VBP15治疗已显示在多种疾病模型（包括TNBS诱导的结肠炎小鼠模型（初步数据））中降低体内炎症活性，并导致更温和的副作用特征。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，与泼尼松龙相反，VBP15降低了疾病严重程度，表明VBP15可能对受损肠上皮的恢复过程具有更良性的作用。因此，在IBD的长期治疗中，VBP15可能代表传统糖皮质激素的更有效，但更安全的替代品。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恢复。因此，鉴定抑制促炎活性并且也不损害肠上皮的有效恢复的化合物可以代表一种治疗剂， 改变炎症性肠病的自然病程。