SBIR-STTR Award

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.

Thesaurus Terms:
2-Deoxy-2-((Methylnitrosoamino)Carbonyl)Amino-D-Glucose;2-Deoxy-2-(3-Methyl-3-Nitrosoureido)-D-Glucopyranose;2-Deoxy-2-[[(Methylnitrosamino)-Carbonyl]amino]-D-Glucopyranose;21+ Years Old;Atgn;Address;Adult;Adult Human;Advanced Glycation End Products;Advanced Glycosylation End Products;Alveolar Bone Loss;Alveolar Resorption;Alveolodental Ligament;Alveolodental Membrane;American;Animal Model;Animal Models And Related Studies;Animals;Anti-Inflammatories;Anti-Inflammatory Agents;Anti-Inflammatory;Anticoagulant Agents;Anticoagulant Drugs;Anticoagulants;Antigens;Antiinflammatories;Antiinflammatory Agents;Atrophic Arthritis;Bacterial Infections;Bacteroides Gingivalis;Blood Glucose;Blood Neutrophil;Blood Polymorphonuclear Neutrophil;Blood Segmented Neutrophil;Blood Sugar;Blood Leukocyte;Blood Monocyte;Body Tissues;Bone Resorption;Breathing;Cardiovascular Diseases;Cell Surface Receptors;Cell-Extracellular Matrix;Chronic;Chronic Periodontitis;Clinical Trials;Closure By Ligation;Connective Tissue;Cutaneous Disorder;Data;Data Collection;Dermatoses;Diabetes Mellitus;Disease Progression;Dose;Drug Formulations;Ecm;Edodekin Alfa;Ethers;Event;Experimental Models;Exposure To;Extracellular Matrix;Fibroblasts;Formulation;Gingiva;Gingival;Gingivitis;Glycans;Glycosaminoglycans;Goals;Gram-Negative Bacteria;Heparin;Heparinic Acid;Heparinoids;Heterophil Granulocyte;Human;Hyaluronic Acid;Il-12;Il12;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Arthritis;Inflammatory Response;Inhalation;Inhaling;Inhibition Of Matrix Metalloproteinases;Inhibition Of Matrix Metalloproteinases Pathway;Inorganic Sulfates;Interleukin-12;Interleukins;Intervention;Intervention Strategies;Investigational New Drug Application;Kidney Diseases;Leukocytes;Leukocytes Reticuloendothelial System;Ligands;Ligation;Lipopolysaccharides;Mmps;Man (Taxonomy);Marketing;Marrow Neutrophil;Marrow Leukocyte;Marrow Monocyte;Matrix Metalloproteinases;Measures;Mediating;Microbial Biofilms;Modeling;Modern Man;Mucopolysaccharides;Nksf;Natural Killer Cell Stimulatory Factor;Nephropathy;Neutrophilic Granulocyte;Neutrophilic Leukocyte;Nuclear;Oral;Osteoclastic Bone Loss;P. Gingivalis;P.Gingivalis;Psgag;Parodontosis;Pathology;Periodontal Bone Loss;Periodontal Diseases;Periodontal Infection;Periodontal Ligament;Periodontal Membrane;Periodontal Pocket;Periodontal Resorption;Periodontitis;Phase;Polymorph;Polymorphonuclear Cell;Polymorphonuclear Leukocytes;Polymorphonuclear Neutrophils;Polysaccharides;Porphyromonas Gingivalis;Pregnancy Complications;Prevention;Prevention Therapy;Production;Proteins;Rat Model Of Diabetes;Renal Disease;Reporting;Respiratory Aspiration;Respiratory Inspiration;Rheumatoid Arthritis;Risk;Sbir;Sbirs (R43/44);Stz;Skin Diseases;Skin Diseases And Manifestations;Small Business Innovation Research;Small Business Innovation Research Grant;Smoker;Smoking;Streptozocin;Streptozotocin;Sulfates;Testing;Therapeutic;Tissues;Tobacco;Tobacco Smoke;Tooth;Tooth Diseases;Tooth Disorder;Tooth Loss;Tooth Structure;Topical Drug Administration;Topical Application;Toxicology;Unspecified Or Sulfate Ion Sulfates;White Blood Cells;White Cell;Work;Zanosar;Adult Human (21+);Adulthood;Advanced Glycation Endproduct;Alveolar Bone;Alveolar Supporting Bone;Bacterial Disease;Base;Biofilm;Blood Thinner;Bone Loss;Cardiovascular Disorder;Clinical Investigation;Cytokine;Dental Disease;Dental Disorder;Diabetes;Diabetic;Diabetic Rat;Diabetic Rat Model;Experiment;Experimental Research;Experimental Study;Gene Product;Glycation;Glycosaminoglycan Polysulfate;Glycosaminoglycan Polysulfuric Acid Ester;Glycosaminoglycan Polysulphate;Immunogen;In Vivo;Inhibitor;Inhibitor/Antagonist;Inspiration;Interventional Strategy;Kidney Disorder;Macrophage;Maxilla Alveolar Process;Meetings;Microbial;Model Organism;Monocyte;Neutrophil;Nonenzymatic Glycosylation;Novel;Pathogen;Periodontal Disorder;Periodontium Disease;Periodontium Disorder;Polysulfated Glycosaminoglycan;Pre-Clinical;Preclinical;Preclinical Safety;Renal Disorder;Research Study;Skin Disorder;Socket Wall;Sulfate;Sulfated Glycosaminoglycan;Teeth;Therapeutic Target;Thrombopoiesis Inhibitor;Tooth Surface;Topical Administration;Topical Drug Application;Topically Applied;White Blood Cell;White Blood Corpuscle

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.

Public Health Relevance Statement:


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.

NIH Spending Category:
Autoimmune Disease; Dental/Oral and Craniofacial Disease; Diabetes; Infectious Diseases; Prevention

Project Terms:
Adult; Advanced Glycosylation End Products; Affect; Alkylation; alveolar bone; Alveolar Bone Loss; American; Anti-inflammatory; Anti-Inflammatory Agents; Bacteria; base; Bone Resorption; Canis familiaris; Cardiovascular Diseases; Characteristics; Chronic; Clinical; Dental; Diabetes Mellitus; diabetic; diabetic rat; Dinoprostone; Dose; Drug Formulations; efficacy testing; Environment; Ethers; Family; Fibroblasts; Functional disorder; Gel; Gelatinase A; Genetic; Gingiva; Gingivitis; Glycosaminoglycans; Haplotypes; high risk; HMGB1 Protein; Human; Hyaluronic Acid; In Situ; In Vitro; in vivo; Individual; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Interstitial Collagenase; ITGAM gene; ITGB2 gene; Kidney Diseases; L-Selectin; Lead; Leukocyte Elastase; Leukocyte L1 Antigen Complex; Leukocytes; Ligands; Ligation; Lipopolysaccharides; Liquid substance; local drug delivery; Local Therapy; macrophage; Macrophage-1 Antigen; Mandible; Mediating; Mediator of activation protein; microbial; Microbial Biofilms; Microspheres; Modeling; monocyte; non-diabetic; Oral cavity; Osteoclasts; Outcome; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Pharmaceutical Preparations; Phase; Population; Porphyromonas gingivalis; Pre-Eclampsia; Prevention strategy; Process; Production; public health relevance; Rattus; receptor; response; Rheumatoid Arthritis; Risk; Risk Factors; scaling and root planing; Smoker; Smoking; soft tissue; sulfation; Testing; Therapeutic; Time; Tissues; TNF gene; TNFSF11 gene; Toll-Like Receptor 2; Tooth Diseases; Tooth Loss; Tooth struc