Anti-Inflammatory Glycosaminoglycan Ethers for Treatment of Periodontitis

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 B producing higher IL 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 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 CR also known as Mac and block interaction of RAGE with its known important ligands including AGEs high mobility group box protein HMGB and S calgranulins In Phase I the GlycoMira team demonstrated that the lead SAGE GM has at least five salutary effects for treating periodontitis First it decreases IL and P gingivalis lipopolysaccharide LPS stimulated IL prostaglandin E and matrix metalloproteinases MMP and release from macrophages and human gingival fibroblasts Second it blocks CR 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 IL and MMP and 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 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 to alter or block osteoclast activation and reduce bone resorption iii test tolerability of topical formulations for delivery of GM 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 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 preeclampsia and pre term delivery We propose to develop anionic partially lipophilic hyaluronic acid derivatives as a simple mechanistically based treatment for this chronic and extraordinarily common dental disorder