NOVEL PARS INHIBITOR FOR THE THERAPY OF COLITIS

炎症性肠病(IBD)是美国人口慢性发病率的主要来源。目前的治疗方案疗效有限，因为没有完全无毒的药物可以完全阻止或逆转IBD的发展。Inote公司建议在特发性结肠炎的确定的亚人类灵长类动物模型中测试新型治疗剂INH2 BP的可行性，该模型展示了临床IBD的经典特征INH2 BP是一种高效的聚(ADP-核糖)合成酶(PARS)的特异性抑制物，PARS是一种核酶，其被炎性氧化应激激活会导致能量耗竭和组织功能障碍。在局部和全身炎症损伤的啮齿动物模型中，PARS抑制剂增加了存活率，阻断了组织损伤，保存了组织能量，减少了中性粒细胞的渗透、前列腺素的形成、体重减轻和粘膜高通透性，在三硝基苯磺酸(TNBS)诱导的结肠炎模型中，抑制PARS完全防止了粘膜损伤，PARS基因敲除的小鼠同样完全免受TNBS诱导的结肠炎的影响。伊诺克现在建议在猕猴结肠炎的特发性模型中建立原则证明，这是通过组织损伤的组织学和生化相关性进行评估的。动物研究将在杜兰地区灵长类研究中心进行，该中心是美国最大的灵长类研究基地。在确认INH2 BP在这种严格的和临床相关的结肠炎模型中有效后，Inote k打算申请NIH SBIR第二阶段资金，以支持正式的毒理学研究和FDA批准的第一阶段临床试验。拟议的商业应用：一种治疗炎症性肠病的新的有效疗法的国内市场估计每年为1.5亿-2亿美元。据估计，全球市场规模为6亿。目前的市场进入者略微有效：慢性结肠炎反复发作，体重减轻，出血，并经常进展为恶性肿瘤。INH2 BP可能代表着第一个高度有效和成功的候选疗法；SBIR第一和第二阶段的资金将允许在3.5年内进入市场。

Inflammatory bowel disease (IBD) is a major source of chronic morbidity in the US population. Current treatment regimens are of limited efficacy, as there are no entirely non-toxic pharmaceuticals which totally halt or reverse the progression of IBD. Inotek Corporation proposes to test the feasibility of a novel therapeutic agent, INH2BP, in a definitive sub-human primate model of idiopathic colitis which demonstrates the classic features of clinical IBD INH2BP is a highly potent specific inhibitor of poly (ADP- ribose) synthetase (PARS), a nuclear enzyme whose activation by inflammatory oxidant stress results in energetic depletion and tissue dysfunction. In rodent models of regional and systemic inflammatory injury, PARS inhibitors increased survival, blocked tissue injury, preserved tissue energetics, and reduced neutrophil infiltration, prostaglandin formation, weight loss, and mucosal hyperpermeability, PARS inhibition in a rodent model of trinitrobenzenesulfonic acid (TNBS)- induced colitis completely prevented mucosal damage, PARS knock-out mice are likewise totally protected from TNBS-induced colitis. Inotek now proposes to establish proof-of-principle in an idiopathic model of colitis in Rhesus macaques, as assessed by histologic and biochemical correlates of tissue injury. Animal studies will be conducted at the Tulane Regional Primate Research Center, the largest primate research colony in the US. Upon confirmation that INH2BP is efficacious in this stringent and clinically relevant model of colitis, Inotek intends to apply for Phase II NIH SBIR funding to support formal toxicologic studies and a Phase I FDA-approved clinical trial. PROPOSED COMMERCIAL APPLICATION: The domestic market for a novel, effective therapy for inflammatory bowel disease is estimated at $150-200 million per annum. Global markets are estimated at 600 million. Current market entrants are marginally effective: Chronic colitis is recurrent, with weight loss, bleeding, and frequent progression to malignancy. INH2BP may represent the first highly potent and successful candidate therapy; funding of SBIR Phases I and II will allow for market entry in 3.5 years.