NOVEL PARS INHIBITOR FOR THE THERAPY OF COLITIS

炎症性肠病（IBD）是美国人群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的进展。Inotek公司提出在特发性结肠炎的确定性亚人灵长类动物模型中测试新型治疗剂INH 2BP的可行性，该模型证明了临床IBD的经典特征。INH 2BP是聚（ADP-核糖）合成酶（PARS）的高效特异性抑制剂，PARS是一种核酶，其被炎性氧化应激激活导致能量消耗和组织功能障碍。在局部和全身性炎性损伤的啮齿动物模型中，PARS抑制剂增加存活、阻断组织损伤、保护组织能量并减少嗜中性粒细胞浸润、前列腺素形成、体重减轻和粘膜通透性过高，PARS抑制在三硝基苯磺酸（TNBS）诱导的结肠炎的啮齿动物模型中完全防止粘膜损伤，PARS敲除小鼠同样完全免受TNBS诱导的结肠炎。Inotek现在提出在恒河猴的特发性结肠炎模型中建立原理验证，通过组织损伤的组织学和生物化学相关性进行评估。动物研究将在杜兰地区灵长类动物研究中心进行，该中心是美国最大的灵长类动物研究中心。在确认INH 2BP在这种严格且临床相关的结肠炎模型中有效后，Inotek打算申请II期NIH SBIR资金，以支持正式的毒理学研究和FDA批准的I期临床试验。拟定商业应用：国内市场的一种新的，有效的治疗炎症性肠病的估计为1.5亿至200亿美元每年。全球市场估计为6亿。目前的市场进入者效果甚微：慢性结肠炎是复发性的，伴有体重减轻、出血和频繁进展为恶性肿瘤。INH 2BP可能是第一个高效和成功的候选疗法; SBIR I期和II期的资金将允许在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.