A Novel Remedy for Periodontal Bone Loss

牙周炎是一种常见的慢性炎症性疾病，其特征是牙周组织的破坏， 牙齿的结构（牙周膜和牙槽骨）。牙周炎的总患病率 30岁及以上的成年人占47.2%（约6470万30岁及以上的成年人） 在美国，65岁及以上的成年人中有70.1%。目前牙周病的治疗选择 涉及机械清创-刮治和根面平整，这需要频繁和多次访问 有时随后进行局部递送抗菌剂或全身递送抗菌剂的连续治疗。 抗生素如强力霉素。目前治疗方案的缺点是不方便和痛苦 根据经验，抗菌剂无法穿透生物膜表面层，促进抗菌剂的风险 耐药性和全身副作用。目前治疗的其他局限性是这些药物中没有一种是 针对宿主和牙周骨流失。有一个主要的空白牙周病治疗产品 其能够针对宿主反应并且易于使用。 全球牙周病治疗市场预计将从2016年到2024年增长8.7%。 按照这个速度，预计到预测期结束时，市场估值将达到5.372亿美元。 Periomics Care是一家位于纽约的早期生物技术公司， 将用于治疗牙周病的新型口服凝胶制剂商业化。在第一阶段， POC 7a是一种靶向琥珀酸受体的拮抗剂制剂，经过合成、配制、测试并获得专利 （SUCNR 1）作为牙周病的治疗。在第二阶段，Periomics Care建议扩大 POC 7a合成和配制以进行POC 7a的药代动力学/药效学和毒性 Beagle犬（Aim 1）。我们将在结扎诱导的非人灵长类动物（NHP）中进一步测试该制剂。 模型，以验证我们的发现，POC 7a有效地挽救牙周骨丢失（目标2）。NHP模型是 最适合这项研究的模型，因为它们在途径方面具有高度相似性， 与人类疾病相关的生理反应和靶点。更重要的是，NHP具有口腔 结构和牙齿与人类相似，并具有天然存在的牙菌斑、牙石、口腔 微生物病原体和发展类似的牙周症状。这项建议的前提是基于我们的 I期研究发现，通过POC 7a阻断SUCNR 1可以减少炎症，改变龈下微生物组， 并挽救骨质流失。第一阶段开发的技术和配方现已受到知识产权保护。资金 从STTR第二阶段赠款中获得的资金将用于（1）合成和测试配方，以及（2） 确定所述制剂在牙周NHP模型中的功效。这项研究的结果将有助于 该公司寻求FDA批准的最佳配方，并进行临床试验的治疗， 预防牙周病。

Periodontitis is a common chronic inflammatory disease characterized by destruction of the supporting structures of the teeth (the periodontal ligament and alveolar bone). The total prevalence of periodontitis in adults aged 30 years and older was 47.2% (representing about 64.7 million adults aged 30 years and older) and 70.1% in adults aged 65 years and older in the U.S. The current treatment option for periodontal diseases involves mechanical debridement – scaling and root planing which requires frequent and multiple visits to the dentist and is sometimes followed by adjunctive therapy of local delivery of antimicrobials or systemic antibiotics such as doxycycline. The disadvantages of current treatment options are inconvenient and painful experience, failure of antimicrobial to penetrate beyond biofilm surface layer, risks to promote antimicrobial resistance, and systemic side effects. Other limitation of current treatment is that none of these drugs are targeting host and periodontal bone loss. There is a major void in periodontal disease therapeutics products which can target host response and is easy to use. The global periodontal disease therapeutics market is anticipated to gain a growth of 8.7% from 2016 to 2024. At this pace, the market is estimated to reach a valuation of US$537.2M by the end of the forecast period. Periomics Care is an early-stage New York based biotechnology company that was established to commercialize a novel oral gel formulation for treatment of periodontal disease. In Phase I we have synthesized, formulated, tested and patented POC7a, an antagonist formulation to target succinate receptor (SUCNR1) as a treatment for periodontal disease. In Phase II Periomics Care proposes to scale up the synthesis and formulation of POC7a to conduct pharmacokinetics/ pharmacodynamics, and toxicity of POC7a in Beagle dogs (Aim1). We will further test this formulation in ligature induced Non-human Primate (NHP) model to validate our finding that POC7a effectively rescues periodontal bone loss (Aim 2). NHP model is the best suitable model for this study because they have a high degree of resemblance in terms of pathways of physiological responses and targets that are relevant to human disease. More importantly NHP have oral structures and teeth similar to those of humans and have naturally occurring dental plaque, calculus, oral microbial pathogens and develop similar periodontal symptoms. The premise of this proposal is based on our findings in Phase I that blocking SUCNR1 by POC7a can reduce inflammation, alter subgingival microbiome and rescue bone loss. The technology and formulation developed in Phase I is now IP protected. The funds gained from this STTR Phase II grant will be used for (1) synthesis and testing of the formulation, and (2) determining the efficacy of the formulation in periodontal NHP model. The outcomes from this study will help the company to seek FDA approval for the optimal formulation and conduct clinical trials for the treatment and prevention of periodontal disease.