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（由申请人提供）：Traverse Biosciences Inc.是一家临床前阶段药物开发公司，致力于将新的化学实体商业化，这些化学实体通过病理学上不受限制的基质金属蛋白酶（MMP）和促炎细胞因子的多效性宿主调节来解决炎症状况该公司的主要候选药物TRB-N0224是一种专有的化学修饰姜黄素，由以下公司的共同发明人开发： Periostat(R) 和 Oracea(R) 是目前 FDA 批准的唯一 MMP 抑制剂牙周病是一种慢性炎症性疾病，涉及口腔细菌产物、宿主组织中的大量细胞群以及炎症介质，例如细胞因子、趋化因子、花生四烯酸代谢物和蛋白水解酶（包括基质金属蛋白酶）共同导致组织破坏和骨吸收。疾病控制中心 (CDC) 估计，美国 30 岁及以上成年人中牙周炎的患病率为 47.2% (64.7M)，轻度、中度和重度牙周炎的患病率为 8.7% (11.9M)、30.0% (41.1M) 和 8.5% (11.7M)牙周病还与其他慢性疾病有关，例如心脏病、糖尿病和各种癌症。主要关注微生物生物膜的管理，没有考虑到在组织损伤中引起炎症的核心作用，这使得该疗法仅部分有效作为广谱 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，可能通过中断 NF-kB 通路来解决炎症。一种多靶点、宿主调节方法，克服了冗余、补偿和免疫系统必然表现出的挑战选择姜黄素作为母体结构，因为它也具有与四环素相似的 1,3-二酮部分，并且我们的长期目标是开发一种有效的诱导型 MMP 抑制剂，其副作用和毒性最小，因此我们进行了化学修饰，以克服姜黄素在临床上的使用有限的问题。显着减少与牙周病相关的并发症。我们的目标是在 LPS 诱导的牙周病大鼠模型中测试我们的先导化合物 TRB-N0224 的功效。我们的第一阶段假设是，在 LPS 诱导的牙周病大鼠模型中，施用 TRB-N0224 将保护牙槽骨免受 MMP 损伤，并降低牙龈组织和血清中促炎物质的水平。我们的具体目标是通过测量距固定解剖标志（牙骨质）的距离来评估我们的先导化合物 TRB-N0224 在 LPS 诱导的大鼠模型中预防和治疗牙周病的有效性。 -牙釉质连接、牙槽骨嵴以及 MMP 和炎症细胞因子的水平/活性也将被评估，第一阶段的成功完成将使我们能够寻求第二阶段的资金来支持临床前测试。 TRB-N0224，利用临床适用的犬牙周病模型，我们希望将 TRB-N0224 商业化，作为 FDA 批准的口服（即全身）制剂治疗牙周病的药物干预措施。 -临床和临床开发，以证明该主要候选药物的安全性和有效性。