Anti-Inflammatory Glycosaminoglycan Ethers for Treatment of Periodontitis

描述(申请人提供)：牙齿周围软组织的慢性牙周炎困扰着超过一半的美国成年人。在受影响最严重的情况下，这种炎症过程发展到更深的牙周韧带和牙槽骨，导致因下颌支抗丧失而导致的牙齿脱落。牙周炎和牙周炎是由 由牙龈假单胞菌等细菌慢性感染引起的牙周炎。患牙周炎的风险是普遍的，但单倍型IL-1B的受试者在 阴沟液、糖尿病患者和吸烟者对细菌生物膜都有更强烈的反应，从而导致严重的牙周病。定期刷牙和使用牙线、半年一次的洁牙和牙根平整以去除菌斑和生物膜对正常人来说是有效的预防策略，但不足以阻止糖尿病等高危人群严重牙周疾病的进展，在糖尿病患者中，糖尿病相关的晚期糖基化终产物(AGEs)与晚期糖基化终产物受体(RAGE)的相互作用会促进牙周炎的加速。在第一阶段，GlycoMira治疗公司描述了一种专利的5 kDa半合成糖胺葡聚糖醚(SAGE)家族，源于透明质酸(HA)的硫化和烷基化，本质上是非抗凝剂。SAGE是一种系统和局部安全的抗炎药，可以阻断P-选择素和L-选择素，抑制人中性粒细胞弹性蛋白酶(HLE)，阻断补体受体-3(CR3，也称为Mac-1)，并阻断RAGE与其已知重要配体的相互作用，包括AGEs、高迁移率族蛋白-1(HMGB-1)和S100钙颗粒蛋白。在第一阶段，GlycoMira团队证明了先导鼠尾草GM-0111至少有五种治疗牙周炎的有益效果。首先，它减少IL-1β和牙龈假单胞菌脂多糖(LPS)刺激的巨噬细胞和人牙龈成纤维细胞释放IL-1、前列腺素E_2和基质金属蛋白酶(MMP1、2、3和9)。其次，它能阻断CR3介导的巨噬细胞对牙龈假单胞菌的内化。第三，抑制牙龈假单胞菌由血单核细胞诱导的多核破骨细胞的形成。第四，降低糖尿病大鼠牙龈提取液中肿瘤坏死因子、白介素1、白介素6、基质金属蛋白酶2和9的水平。最后，也是最重要的一点是，在糖尿病大鼠牙周加速疾病模型中，当非肠道给药时，它可以抑制牙槽骨丢失。在第二阶段，GlycoMira将测试 GM-0111可作为牙周病局部有效治疗的假说。我们建议(I)使用糖尿病大鼠模型显示局部给药的有效性，(Ii)探讨GM-0111改变或阻断破骨细胞激活和减少骨吸收的能力，(Iii)在Beagle犬进行剂量范围研究中测试GM-0111局部给药制剂的耐受性，(Iv)在Beagle狗身上进行关键研究，以测试所选处方的有效性。

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.