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

 描述（由申请人提供）：Traverse Biosciences Inc.是一家临床前阶段的药物开发公司，致力于商业化新的化学实体，其通过病理上不受限制的基质金属蛋白酶（MMP）和促炎细胞因子的多效宿主调节来解决炎症状况。该公司的主要候选药物TRB-N 0224是一种专有的化学修饰姜黄素，由Periostat（R）和Oracea（R）的联合发明人开发，这是目前唯一获得FDA批准的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和炎症介质（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））之间的相互作用，这些炎症介质共同导致组织破坏和骨吸收。疾病控制中心（CDC）估计，美国30岁及以上成年人的牙周炎患病率为47.2%（64.7 M），轻度、中度和重度牙周炎的患病率分别为8.7%（11.9 M）、30.0%（41.1 M）和8.5%（11.7 M）。牙周病也与其他慢性疾病有关，如心脏病、糖尿病和各种癌症。目前大多数药物疗法主要集中在微生物生物膜的管理上，而没有考虑炎症在引起组织损伤中的核心作用，这使得这种疗法仅部分有效。TRB-N 0224作为广谱MMP调节剂以及促炎细胞因子如IL 1-B、TNF-α和IL-6的抑制剂表现出多效性抗炎作用，这可能是通过中断NF-κ B途径实现的。TRB-N 0224通过多靶点、宿主调节方法来解决炎症，该方法克服了免疫系统表现出的冗余、补偿和必要性的挑战。选择姜黄素作为母体结构，因为它也具有与四环素类似的1，3-二酮基部分，并且进行化学修饰以克服姜黄素由于其不溶性而限制的临床应用，快速代谢和适度的生物活性。我们的长期目标是开发一种有效的诱导型MMPs抑制剂，具有最小的副作用和毒性，将显着减少与牙周病相关的并发症。这里的目标，这是我们追求目标的下一步，是测试我们的先导化合物TRB-N 0224在LPS诱导的牙周病大鼠模型中的疗效。我们的I期假设是，在LPS诱导的牙周病大鼠模型中，施用TRB-N 0224将保护牙槽骨免受MMP损伤，并降低牙龈组织和促炎介质的血清水平。我们的具体目标是使用LPS诱导的大鼠模型评估我们的先导化合物TRB-N 0224预防和治疗牙周病的有效性。将通过测量从固定的解剖标志牙骨质-釉质连接处到牙槽骨嵴的距离来确定骨丢失，还将评估MMP和炎性细胞因子的水平/活性。第一阶段的成功完成将使我们能够寻求第二阶段的资金，以支持TRB-N 0224的临床前测试，利用临床适用的牙周病犬模型。我们希望将TRB-N 0224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，并打算进行临床前和临床开发，以证明这种先导候选药物的安全性和有效性。

 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.