Evaluation of TRB-N0224, a Proprietary Chemically Modified Curcumin, for the Treatment of Periodontal Disease in a LPS-Induced Rat Model

TRB-N0224（一种专有的化学修饰姜黄素）在 LPS 诱导的大鼠模型中治疗牙周病的评估

基本信息

批准号：
8834328
负责人：
YING GU
金额：
$ 20.57万
依托单位：
TRAVERSE BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2016-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Traverse Biosciences Inc. is a pre-clinical stage drug development company working to commercialize new chemical entities which act to resolve inflammatory conditions through pleiotropic host-modulation of pathologically unrestrained matrix metalloproteinases (MMPs) and pro-inflammatory cytokines. The company's lead drug candidate, TRB-N0224, is a proprietary chemically modified curcumin developed by the co-inventor of Periostat(R) and Oracea(R), currently the only FDA-approved MMP inhibitors. Periodontal disease is a chronic inflammatory condition involving interactions between oral bacterial products, numerous cell populations in the host tissues, and inflammatory mediators, such as cytokines, chemokines, arachidonic acid metabolites and proteolytic enzymes (including matrix metalloproteinases), which collectively contribute to tissue destruction and bone resorption. The Centers for Disease Control (CDC) estimates that the prevalence of periodontitis in U.S. adults aged 30 years and older is 47.2% (64.7M), and the prevalence of mild, moderate, and severe periodontitis is 8.7% (11.9M), 30.0% (41.1M), and 8.5% (11.7M), respectively. Periodontal disease has also been associated with other chronic conditions such as heart disease, diabetes, and various cancers. Most current drug therapies are primarily focused on the management of the microbial biofilm, not taking into account the central role of inflammation in causing tissue damage, which makes this therapy only partly effective. TRB-N0224 exhibits pleiotropic anti-inflammatory effects as a broad-spectrum MMP modulator, as well as an inhibitor of pro-inflammatory cytokines such as IL1-b, TNF-a, and IL-6, likely through interruption of the NF-kB pathway. TRB-N0224 acts to resolve inflammation via a multi-target, host-modulatory approach that overcomes the challenges of redundancy, compensation and necessity exhibited by the immune system Curcumin was chosen as a parent structure because it also has a 1,3-diketo moiety similar to that of the tetracyclines, and chemical modifications were pursued to overcome limited clinical use of curcumin due to its insolubility, rapid metabolism and modest biological activity. Our long-term goal is to develop an effective inhibitor of inducible MMPs with minimal side effects and toxicity that will significantly reduce the complications associated with periodontal disease. The objective here, which is the next step in the pursuit of our goal, is to test the efficacy of our lead compound, TRB-N0224, in a LPS-induced rat model of periodontal disease. Our Phase I Hypothesis is that administration of TRB-N0224 will protect alveolar bone from MMP damage in a LPS-induced rat model of periodontal disease, and lower the gingival tissue and serum levels of pro- inflammatory mediators. Our specific aims are to evaluate the effectiveness of our lead compound, TRB- N0224, to prevent and treat periodontal disease using a LPS-induced rat model. Bone loss will be determined by measuring the distance from a fixed anatomical landmark, the cemento-enamel junction, to the alveolar bone crest, and levels/activity of MMPs and inflammatory cytokines will also be assessed. Successful completion of Phase I will allow us to pursue Phase II funding to support pre-clinical testing of TRB-N0224, utilizing a clinically applicable canine model of periodontal disease. We hope to commercialize TRB-N0224 as an FDA-approved pharmaceutical intervention for the treatment of periodontal disease in an orally-administer (i.e. systemic) formulation, and intend to pursue pre-clinical and clinical development to demonstrate the safety and efficacy of this lead drug candidate.

描述（由应用提供）：Traverse Biosciences Inc.是一家临床前的药物开发公司，致力于将新的化学实体商业化，该公司通过对病理不受限制的金属蛋白酶（MMPS）和促炎细胞因子的病理不受限制的基质金属蛋白酶（MMP）和促炎细胞因子来解决炎症条件。该公司的主要候选药物TRB-N0224是由Pererostat（R）和Oracea（R）共同开发的专有化学修饰的姜黄素，目前是FDA批准的MMP抑制剂。牙周疾病是一种慢性炎症疾病，涉及口服细菌产物之间的相互作用，宿主组织中的许多细胞群以及炎性介质（例如细胞因子，趋化因子，花生四烯酸代谢产物和蛋白水解酶）（包括Matrix金属蛋白酶）（包括综合造成了骨骼脱落和骨骼脱落）。疾病控制中心（CDC）估计，30岁及30岁以上的美国成年人的牙周炎患病率为47.2％（64.70万），轻度，中度和严重牙周炎的患病率分别为8.7％（1190万），30.0％（41.1m1m）和8.5％（11.7m）。牙周病也与其他慢性病有关，例如心脏病，糖尿病和各种癌症。当前大多数药物疗法主要集中于微生物生物膜的管理，而不是考虑到炎症在造成组织损伤中的核心作用，这使得这种疗法仅部分有效。 TRB-N0224表现出多光谱MMP调节剂以及促炎细胞因子（例如IL1-B，TNF-A和IL-6）的抑制剂，表现出多效性抗炎作用，可能是通过中断NF-KBB途径的中断。 TRB-N0224 acts to resolve inflammation via a multi-target, host-modulatory approach that overcomes the challenges of redundancy, compensation and necessary experience by the immune system Curcumin was chosen as a parent structure because it also has a 1,3-diketo moiety similar to that of the tetracyclines, and chemical modifications were pursued to overcoming limited clinical use of curcumin due to its insolvability, rapid代谢和适中的生物学活性。我们的长期目标是开发具有最小副作用和毒性的诱导型MMP的有效抑制剂，这将显着减少与牙周疾病相关的并发症。这里的目标是追求我们目标的下一步，是在LPS诱导的牙周疾病大鼠模型中测试我们铅化合物TRB-N0224的有效性。我们的I阶段假设是，在LPS诱导的牙周疾病大鼠模型中，TRB-N0224的给药将保护肺泡骨免受MMP损伤，并降低牙龈组织和促炎性介体的血清水平。我们的具体目的是评估我们的铅化合物TRB-N0224的有效性，以使用LPS诱导的大鼠模型来预防和治疗牙周疾病。骨质流失将通过测量从固定的解剖学地标，水泥 - 云母连接到肺泡骨波峰的距离，以及MMP和炎症细胞因子的水平/活性也将得到评估。成功完成I期的完成将允许我们购买II期资金，以支持TRB-N0224的临床前测试，并利用临床适用的牙周疾病模型。我们希望将TRB-N0224商业化为FDA批准的药物干预措施，用于在口服Administer（即全身性）配方中治疗牙周疾病，并打算购买临时和临床开发，以证明该主要药物候选人的安全性和效率。