Anti-Inflammatory Glycosaminoglycan Ethers for Treatment of Periodontitis

用于治疗牙周炎的抗炎糖胺聚糖醚

• 批准号: 8737875
• 负责人: Won Yong Lee
• 金额: $ 68.52万
• 依托单位: GLYCOMIRA, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737875
• 关键词: Adult; Advanced Glycosylation End Products; Affect; Alkylation; Alveolar Bone Loss; American; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Bone Resorption; Canis familiaris; Cardiovascular Diseases; Characteristics; Chronic; Clinical; Dental; Diabetes Mellitus; Dinoprostone; Dose; Drug Formulations; Environment; Ethers; Family; Fibroblasts; Functional disorder; Gel; Gelatinase A; Genetic; Gingiva; Gingivitis; Glycosaminoglycans; HMGB1 Protein; Haplotypes; Human; Hyaluronic Acid; ITGAM gene; ITGB2 gene; In Situ; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Interstitial Collagenase; Kidney Diseases; L-Selectin; Lead; Leukocyte Elastase; Leukocyte L1 Antigen Complex; Leukocytes; Ligands; Ligation; Lipopolysaccharides; Liquid substance; Local Therapy; Macrophage-1 Antigen; Mandible; Mediating; Mediator of activation protein; Microbial Biofilms; Microspheres; Modeling; Oral cavity; Osteoclasts; Outcome; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Pharmaceutical Preparations; Phase; Population; Porphyromonas gingivalis; Pre-Eclampsia; Prevention strategy; Process; Production; Rattus; Rheumatoid Arthritis; Risk; Risk Factors; Smoker; Smoking; TNF gene; TNFSF11 gene; Testing; Therapeutic; Time; Tissues; Toll-Like Receptor 2; Tooth Diseases; Tooth Loss; Tooth structure; alveolar bone; base; diabetic; diabetic rat; efficacy testing; high risk; in vivo; local drug delivery; macrophage; microbial; monocyte; non-diabetic; public health relevance; receptor; response; scaling and root planing; soft tissue; sulfation

DESCRIPTION (provided by applicant): Chronic gingival inflammation of the soft tissue surrounding the tooth afflicts over half of all American adults. In the most severely affected, progression of this inflammatory process to the deeper periodontal ligaments and alveolar bone results in tooth loss from loss of mandibular anchorage. Gingivitis and periodontitis are initiated by chronic infection of the gingival crevice with bacteria such as Porphryomonas gingivalis. Risk for gingivitis is universal, but subjects with haplotypes of IL-1B producing higher IL-1¿ levels in crevicular fluid, diabetics and smokers all have a more exuberant response to bacterial biofilm leading to serious periodontal disease. Regular brushing and flossing, and semi-annual scaling and root planing to remove plaque and biofilm are effective preventative strategies in normal individuals, but are inadequate to stop progression of serious periodontal disease in high-risk subjects such as diabetics, in whom interaction of diabetes-related advanced glycation end-products (AGEs) with the receptor for advanced glycation end- products (RAGE) promotes accelerated periodontal inflammation. In Phase I, GlycoMira Therapeutics described a proprietary family of 5 kDa semi-synthetic glycosaminoglycan ethers (SAGEs), derived from sulfation and alkylation of hyaluronic acid (HA), that are intrinsically non-anticoagulant. SAGEs are systemically and topically safe anti-inflammatory agents that block P- and L-selectin, inhibit human neutrophil elastase (HLE), block complement receptor-3 (CR3, also known as Mac-1), and block interaction of RAGE with its known important ligands, including AGEs, high mobility group box-1 protein (HMGB-1) and S100 calgranulins. In Phase I, the GlycoMira team demonstrated that the lead SAGE, GM-0111, has at least five salutary effects for treating periodontitis. First, it decreases IL-1¿- and P. gingivalis lipopolysaccharide (LPS)-stimulated IL-1¿, prostaglandin E2, and matrix metalloproteinases (MMP) 1, 2, 3, and 9 release from macrophages and human gingival fibroblasts. Second, it blocks CR3-mediated internalization of P. gingivalis by macrophages. Third, it inhibits P. gingivalis LPS-induced formation of multinucleated osteoclasts from blood monocytes. Fourth, it reduces TNF-¿, IL-1¿, IL-6, and MMP-2 and -9 levels in gingival extracts from diabetic P. gingivalis-infected rats. Finally, and most importantly, it inhibits alveolar bone loss when administered parenterally in a diabetic P. gingivalis-infected rat model of accelerated periodontal disease. In Phase II, GlycoMira will test the hypothesis that GM-0111, can be an effective local therapy for periodontal disease. We propose to (i) use the diabetic rat model to show efficacy of local administration, (ii) explore th ability of GM-0111 to alter or block osteoclast activation and reduce bone resorption, (iii) test tolerability of topical formulations for delivery of GM-0111 into the sulcus in dose-ranging studie in beagle dogs, and (iv) conduct a pivotal study in beagle dogs to test the efficacy of the selected formulation.

描述（由申请人提供）：牙齿周围软组织的慢性牙龈炎症困扰着超过一半的美国成年人。在最严重的影响，这种炎症过程的进展，以更深的牙周韧带和牙槽骨的结果，牙齿损失的损失下颌支抗。牙龈炎和牙周炎是由 通过细菌如牙龈卟啉单胞菌对牙龈缝隙的慢性感染。牙龈炎的风险是普遍的，但具有IL-1B单倍型的受试者产生更高的IL-1水平， 牙槽液，糖尿病患者和吸烟者都对细菌生物膜有更强烈的反应，导致严重的牙周病。定期刷牙和使用牙线，以及半年一次的刮治和根面平整以去除牙菌斑和生物膜是正常个体中的有效预防策略，但不足以阻止高风险受试者如糖尿病患者中严重牙周病的进展，在这些受试者中，糖尿病相关的晚期糖基化终产物（AGEs）与晚期糖基化终产物（AGEs）的受体的相互作用促进加速牙周炎症。 在I期，GlycoMira Therapeutics描述了一个专有的5 kDa半合成糖胺聚糖醚（SAGE）家族，来源于透明质酸（HA）的硫酸化和烷基化，本质上是非抗凝剂。SAGE是全身和局部安全的抗炎剂，其阻断P-和L-选择素，抑制人嗜中性粒细胞弹性蛋白酶（HLE），阻断补体受体-3（CR 3，也称为Mac-1），并阻断补体与其已知的重要配体（包括AGEs、高迁移率族蛋白盒-1蛋白（HMGB-1）和S100钙颗粒蛋白）的相互作用。在第一阶段，GlycoMira团队证明了领先的SAGE GM-0111对治疗牙周炎至少有五种有益的效果。首先，它减少了巨噬细胞和人牙龈成纤维细胞释放的IL-1 <$和牙龈卟啉单胞菌脂多糖（LPS）刺激的IL-1 <$、前列腺素E2和基质金属蛋白酶（MMP）1、2、3和9。第二，它阻断巨噬细胞对牙龈卟啉单胞菌的CR 3介导的内化。第三，它抑制牙龈卟啉单胞菌LPS诱导的从血液单核细胞形成多核破骨细胞。第四，它降低糖尿病牙龈卟啉单胞菌感染大鼠牙龈提取物中TNF-α、IL-1 β、IL-6和MMP-2和MMP-9的水平。最后，也是最重要的是，当在糖尿病牙龈卟啉单胞菌感染的加速牙周病大鼠模型中胃肠外给药时，它抑制牙槽骨丢失。 在第二阶段，GlycoMira将测试 假设GM-0111，可以是一种有效的局部治疗牙周病。我们建议（i）使用糖尿病大鼠模型来显示局部给药的功效，（ii）探索GM-0111改变或阻断破骨细胞活化和减少骨吸收的能力，（iii）在比格犬的剂量范围研究中测试用于将GM-0111递送到沟中的局部制剂的耐受性，和（iv）在比格犬中进行关键研究以测试所选制剂的功效。