Anti-Inflammatory Glycosaminoglycan Ethers for Treatment of Periodontitis

描述(申请人提供)：慢性牙周炎困扰着超过一半的美国成年人，并可发展为牙周病，最终导致牙齿脱落。牙周炎是由牙周组织的细菌感染引起的，细菌通过牙面上的微生物膜释放细菌脂多糖(LPS)和其他抗原。反过来，内毒素诱导白细胞和单核细胞介导的炎症，导致牙龈组织破坏和牙槽骨吸收。牙周缝隙加深形成牙周袋，牙周膜被破坏，受影响的牙齿失去附着。值得注意的是，牙周感染和炎症会大大增加全身疾病的风险，包括心血管和肾脏疾病以及妊娠并发症。糖尿病患者和吸烟者由于接触晚期糖基化终末产物(AGEs)而加重牙周疾病，晚期糖基化终末产物(AGEs)是由蛋白质的自发糖基化引起的。由于高血糖或吸入烟草产品中的AGEs，AGEs通过连接AGEs的细胞表面受体或RAGE而放大炎症。最近，RAGE介导的炎症被认为与牙周炎和破骨细胞源性骨丢失有关。由于阻断RAGE可抑制糖尿病动物牙周炎相关的牙槽骨丢失，RAGE是牙周病干预的一个有吸引力的靶点。硫酸糖胺聚糖(GAG，如肝素)可阻断年龄及其其他配体对RAGE的结扎作用。GAG还展示了其他有益于治疗牙周炎的活性，包括防止革兰氏阴性细菌附着，破坏革兰氏阴性微生物生物膜的形成，抑制内毒素刺激的单核细胞分泌细胞因子，以及抑制白细胞介素12(IL-12)刺激的牙龈成纤维细胞产生基质金属蛋白酶(MMPs)。GlycoMira正在开发半合成糖胺葡聚糖醚(SAGE)，作为安全有效的RAGE炎症调节抑制剂。具体地说，在这个第一阶段的SBIR项目中，我们将从两个特定的目标来确定将SAGES用作牙周炎和牙周炎的新疗法的可行性。首先，我们将测试SAGES在体外抑制与牙周疾病相关的炎症事件的能力，包括牙龈卟啉单胞菌生物膜的形成，内毒素或AGE刺激的人单核/巨噬细胞产生细胞因子，IL-12刺激的人牙龈成纤维细胞产生基质金属蛋白酶，以及AGE诱导的牙龈成纤维细胞产生细胞外基质的抑制。其次，我们将使用牙周炎加速和牙槽骨丢失的模型，在体内测试SAGES的治疗潜力，该模型是牙周炎螺旋体感染、链脲佐菌素诱导的糖尿病大鼠。GlycoMira与世界级执业牙周科医生团队合作，建立临床前数据收集的实验模型，目标是提交研究新药申请(IND)，作为第二阶段项目的里程碑。 与公共卫生相关：超过一半的美国成年人患有慢性牙周炎，发展成明显的牙周病，并导致牙齿脱落。牙周炎是由牙周炎引起的，感染的原因是牙周缝隙的感染和龈下菌斑的产生，从而导致白细胞介导的炎症和牙槽骨的吸收。重要的是，糖尿病和吸烟会加剧牙周病，牙周炎会大大增加心血管和肾脏疾病、类风湿性关节炎和妊娠并发症等系统性疾病的风险。我们建议开发阴离子，部分亲脂的透明质酸衍生物作为一种简单的机械基础上的治疗这种慢性非常常见的牙病。

DESCRIPTION (provided by applicant): Chronic gingival inflammation afflicts over half of all American adults and can progress to periodontal disease, eventually resulting in tooth loss. Periodontitis is initiated by bacterial infection of the gingival tissues through a subgingival microbial biofilm on the tooth surface that releases bacterial lipopolysaccharide (LPS) and other antigens. In turn, LPS induces leukocyte and monocyte-mediated inflammation that causes gingival tissue destruction and alveolar bone resorption. The gingival crevice deepens into a periodontal pocket, the periodontal ligament is destroyed, and the involved tooth loses attachment. Notably, periodontal infection and inflammation can substantially increase the risk of systemic conditions, including cardiovascular and renal diseases, and pregnancy complications. Periodontal disease is exacerbated in diabetics and smokers due to increased exposure to advanced glycation end-products (AGEs), which arise from spontaneous glycation of proteins. AGEs from high blood sugar or from inhalation of AGES from tobacco products amplify inflammation by ligation of the cell-surface receptor for AGEs, or RAGE. Recently, RAGE-mediated inflammation has been implicated in periodontal inflammation and osteoclastogenic bone loss. Since blockade of RAGE inhibits periodontitis-associated alveolar bone loss in diabetic animals, RAGE is an attractive target for intervention in periodontal disease. Sulfated glycosaminoglycans (GAGs, e.g., heparin) block ligation of RAGE by AGE and its other ligands. GAGs show other activities that could also be beneficial in treating gingivitis, including prevention of gram-negative bacteria attachment, disruption of gram negative microbial biofilm formation, inhibition of cytokine secretion by LPS-stimulated monocytes, and inhibition of matrix metalloproteinase (MMP) production by interleukin-12 (IL-12)-stimulated gingival fibroblasts. GlycoMira is developing semi-synthetic glycosaminoglycan ethers (SAGEs) as safe and effective inflammation-modulating inhibitors of RAGE. Specifically, in this Phase I SBIR project, we will establish the feasibility of using SAGEs as a novel therapy for gingivitis and periodontitis in two Specific Aims. First, we will test the ability of SAGEs to inhibit inflammatory events relevant to periodontal diseases in vitro, including biofilm formation by Porphyromonas gingivalis, cytokine production by LPS- or AGE-stimulated human monocyte/macrophages, matrix metalloproteinase production by IL-12-stimulated human gingival fibroblasts, and AGE-induced inhibition of extracellular matrix production by gingival fibroblasts. Second, we will test the therapeutic potential of SAGEs in vivo using a model of accelerated periodontal inflammation and alveolar bone loss, the P. gingivalis-infected, streptozotocin-induced diabetic rat. GlycoMira works with a world-class team of practicing periodontists on experimental models for preclinical data collection, with the goal of filing an Investigational New Drug Application (IND) as a milestone for the Phase II project. PUBLIC HEALTH RELEVANCE: Chronic gingival inflammation afflicts over half of all American adults, evolves into frank periodontal disease, and results in tooth loss. Periodontitis is caused by infection of the gingival crevice and production of subgingival microbial plaque, which results in leukocyte-mediated inflammation and alveolar bone resorption. Importantly, periodontal disease is exacerbated by diabetes and smoking, and periodontitis substantially increases the risk of systemic illness such as cardiovascular and renal disease, rheumatoid arthritis, and pregnancy complications. We propose to develop anionic, partially lipophilic hyaluronic acid derivatives as a simple mechanistically-based treatment for this chronic extraordinarily common dental disorder.