Anti-Inflammatory Glycosaminoglycan Ethers for Treatment of Periodontitis

描述（由申请人提供）：慢性牙龈炎症困扰着超过一半的美国成年人，并可能发展为牙周病，最终导致牙齿脱落。牙周炎是由牙龈组织的细菌感染通过牙齿表面上的龈下微生物生物膜释放细菌脂多糖（LPS）和其他抗原而引发的。反过来，LPS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。牙龈裂隙加深到牙周袋，牙周膜被破坏，并且所涉及的牙齿失去附着。值得注意的是，牙周感染和炎症会大大增加全身性疾病的风险，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暴露于晚期糖基化终产物（AGEs）（由蛋白质的自发糖基化引起）而加重了牙周病。来自高血糖或烟草制品中AGES的吸入的AGEs通过连接AGEs的细胞表面受体或AGEs而放大炎症。最近，RAGE介导的炎症已被牵连在牙周炎症和破骨细胞性骨丢失。由于阻断牙周炎抑制糖尿病动物牙周炎相关的牙槽骨丢失，牙周炎是牙周病干预的一个有吸引力的目标。 硫酸化糖胺聚糖（GAG，例如，肝素）阻断AGE及其其它配体对血管内皮细胞连接。GAG显示出其他活性，这些活性也可能有益于治疗牙龈炎，包括预防革兰氏阴性细菌附着、破坏革兰氏阴性微生物生物膜形成、抑制LPS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（MMP）。 GlycoMira正在开发半合成糖胺聚糖醚（SAGE）作为安全有效的炎症调节抑制剂。具体而言，在第一阶段SBIR项目中，我们将确定在两个特定目标中使用SAGE作为牙龈炎和牙周炎的新疗法的可行性。首先，我们将测试SAGE在体外抑制与牙周病相关的炎症事件的能力，包括牙龈卟啉单胞菌的生物膜形成、LPS或AGE刺激的人单核细胞/巨噬细胞的细胞因子产生、IL-12刺激的人牙龈成纤维细胞的基质金属蛋白酶产生以及牙龈成纤维细胞的细胞外基质产生的AGE诱导的抑制。其次，我们将使用加速牙周炎症和牙槽骨丢失的模型，牙龈卟啉单胞菌感染的链脲佐菌素诱导的糖尿病大鼠，测试SAGE在体内的治疗潜力。GlycoMira与世界一流的牙周病医生团队合作，研究临床前数据收集的实验模型，目标是提交研究性新药申请（IND），作为II期项目的里程碑。 公共卫生相关性：慢性牙龈炎症折磨着超过一半的美国成年人，演变成坦率的牙周病，并导致牙齿脱落。牙周炎是由龈沟感染和龈下菌斑的产生引起的，其导致白细胞介导的炎症和牙槽骨吸收。重要的是，糖尿病和吸烟会加剧牙周病，牙周炎会大大增加全身性疾病的风险，如心血管和肾脏疾病，类风湿性关节炎和妊娠并发症。我们建议开发阴离子，部分亲脂性透明质酸衍生物作为一种简单的机械为基础的治疗这种慢性非常常见的牙科疾病。

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.