SBIR-STTR Award

This proposal aims to develop a therapeutic capable of preventing and treating the severe sinus inflammation associated with chronic rhinosinusitis (CRS). CRS is a debilitating inflammatory disease of the sinuses that impacts over 40 million Americans and substantially diminishes the quality of life and productivity of affected patients. From 2007 to 2011, the total US health care expenditure to treat patients with CRS increased from $9 to $64 billion USD, with a corresponding rise in surgical treatment for those patients who fail current medical management. CRS is characterized by massive inflammatory cell infiltration and increased cytokine/chemokine production. Therapy development should therefore be focused on inhibiting the mechanisms underlying the initiation of these inflammatory responses with the ability to be delivered efficiently by high volume saline irrigation known to improve mucosal penetration. GlycoMira Therapeutics, Inc. (GMTI) is developing a glycosaminoglycan-based anti-inflammatory compound (GM-0111) for CRS that is polyanionic, giving it excellent solubility in saline. Our work has shown that GM-0111 is safe, efficiently penetrates the sinuses, and effectively prevents acute sinus inflammation by blocking neutrophil activation and mast cell infiltration into the sinus mucosa. GM-0111 additionally inhibits important early pro-inflammatory signaling molecules, such as Toll-like receptors and selectins, resulting in decreased inflammatory mediator production. Based on our findings, we hypothesize that GM-0111 can prevent the development and progression of CRS by inhibiting inflammatory cell chemotaxis and activation within the sinuses, thereby reducing inflammation. Chemokines RANTES and eotaxin-2 are elevated in patients with CRS and are important in recruiting mast cells (early effector cells) and eosinophils (late effector cells), which favor a therapeutic-resistant state of inflammation. We will first test our hypothesis (Aim 1) by determining whether GM-0111 can inhibit chemokine-mediated activation of human mast cells, eosinophilic cells, and chemokine receptor knockdown cells (negative control), measuring intracellular calcium flux, proliferation, and chemotaxis in the absence and presence of recombinant chemokine. These studies will provide inflammatory mechanism-focused results for therapy translation to CRS. We will then test the feasibility of GM-0111 to prevent and treat CRS in vivo using a mouse model of CRS (Aim 2). Applying two dosing regimens, we will approach this goal by administering GM-0111 (1) prior to and (2) after establishing chronic sinus inflammation. Sinus tissues will be examined for histological characteristics (inflammatory cell infiltration, secretory cell hyperplasia, mucous secretion, and mucosa thickening) and tissue inflammatory biomarkers (mast cell tryptase, eosinophil myeloperoxidase, RANTES, and eotaxin-2). These studies will provide crucial preclinical data supporting GM-0111 as a therapeutic aimed at preventing and treating sinus inflammation in patients with CRS, moving towards commercialization in a market with tremendous unmet needs to improve the lives of millions of Americans.

Public Health Relevance Statement:
PROJECT NARRATIVE Chronic rhinosinusitius (CRS) is a debilitating disease of sinus inflammation that substantially diminishes the quality of life and productivity of over 40 million Americans, resulting in an annual economic burden of $64 billion USD. The currently available therapies for CRS fail to control the inflammation in 1 of every 5 patients, leaving surgery as the alternative treatment. We have developed a compound that efficiently coats the sinuses and effectively inhibits multiple inflammatory events and factors underlying the mechanisms that favor inflammation. Having important implications for patients, physicians, and public policymakers alike, we will develop this compound into a therapeutic that is capable of preventing and treating CRS, improving the lives of millions of Americans.

Project Terms:
Acute; Affect; Allergens; Alternative Therapies; alternative treatment; American; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Aspergillus fumigatus; base; Binding; Biochemical; Biological Assay; Biological Markers; Cells; Characteristics; chemokine; chemokine receptor; Chemotaxis; Chronic; Chronic Disease; chronic rhinosinusitis; Cognition; commercialization; Complex; Congestive Heart Failure; Coronary heart disease; cytokine; Data; Development; Disease; Dose; Economic Burden; effective therapy; Effector Cell; eosinophil; Etiology; Event; experience; FDA approved; Functional disorder; Glycosaminoglycans; Goals; Health Expenditures; Human; Hyperplasia; Immune; improved; in vivo; In-Migration; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; inflammatory marker; Inflammatory Response; Irrigation; knock-down; Left; Marketing; mast cell; Measures; Mediating; Medical; Mental Depression; mouse model; Mucous body substance; Mucous Membrane; neutrophil; Neutrophil Activation; novel; novel therapeutics; Operative Surgical Procedures; Pathogenesis; Patients; Penetration; Peroxidases; Pharmaceutical Preparations; Physicians; Population; pre-clinical; Prevalence; prevent; Production; Productivity; Quality of life; RANTES; Recombinant Chemokine; Recruitment Activity; Regimen; release of sequestered calcium ion into cytoplasm; Resistance; Saline; Secretory Cell; Selectins; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Sinus; Sleep; Small inducible cytokine A24; Smell Perception; Solubility; Staging; Testing; Therapeutic; Therapeutic Effect; therapy development; Tissues; Toll-like receptors; Translations; Tryptase; Viral; Work

Chronic rhinosinusitis (CRS) is one of the most prevalent inflammatory diseases in the U.S., affecting up to 16% of the population and substantially diminishing the quality of life and productivity of patients. In four years, the annual U.S. health care expenditure to treat patients with CRS dramatically increased from $9B to $64B (5% of the health care budget), with a corresponding rise in surgical treatment for those 20% of patients who fail current medical management. Despite these staggering statistics, CRS remains an under-researched epidemic with limited effective treatment options. GlycoMira’s lead candidate, GM-1111, is a synthetic glycosaminoglycan that inhibits multiple inflammatory mediators and more specifically, targets Toll-like receptor 2-mediated signaling. Moreover, topical intranasal administration of GM-1111 effectively reduces chronic sinonasal inflammation in mice. Animals treated with GM-1111 showed significant reductions in degenerative histologic changes, inflammatory cell infiltration, goblet cell hyperplasia, and cytokine gene expression within the sinonasal tissues. Herein, GM-1111 will be further developed and validated as a commercially viable and effective therapy for CRS. In Aim 1, the optimal dosing regimen and degree to which GM-1111 effectively treats CRS will be determined by testing a wide range of doses and dosing frequencies in animal models of CRS. The efficacy of GM-1111 will be compared to healthy, inflammatory, and therapeutic controls by analyzing the clinical signs, histologic changes, and inflammatory tissue biomarkers associated with CRS. In Aim 2, the potential mucolytic properties of GM-1111 will be investigated, and the effect of GM-1111 on ciliary function will be determined. Increased mucus production and impaired mucociliary clearance are central to the pathogenesis of CRS and elevate the risk of opportunistic pathogen infection. Based on mechanistic evidence with a similar glycosaminoglycan, topically administered GM-1111 should penetrate mucus and reduce sinonasal inflammation. To test this hypothesis, the effects of GM-1111 on artificial mucus with known mucin and bacterial composition, nasal secretions from patients with CRS, and ciliary function using sinonasal tissue from controls and patients with CRS will be investigated. The efficiency of GM-1111 to penetrate mucus and tissue to effectively reduce sinonasal inflammation will then be determined in an animal model of CRS characterized by a robust mucus response. These studies will provide crucial preclinical data supporting GM- 1111 as a commercially viable and effective therapeutic for treating the millions of patients affected by this debilitating disease.

Public Health Relevance Statement:
PROJECT NARRATIVE GlycoMira Therapeutics is developing an effective treatment for chronic rhinosinusitis, a debilitating inflammatory disease that substantially diminishes the quality of life and productivity of up to 16% of the U.S. population and requires $64B annually in direct costs to treat patients. Currently available therapies fail to help 20% of patients with chronic rhinosinusitis, underscoring the dire need for new therapeutics that can improve the lives of millions of Americans.

Project Terms:
Address; Adrenal Cortex Hormones; Adverse effects; Affect; Allergic; American; Animal Model; Animals; Anti-Bacterial Agents; Antibiotics; Architecture; Aspergillus fumigatus; base; Behavior; Biological; Budgets; cell type; Cells; chemokine; Chemotaxis; Chronic; chronic rhinosinusitis; Clinical; Clinical Trials; Complex; cost; Cytokine Gene; Data; Data Files; Direct Costs; Disease; disorder control; Dose; drug development; effective therapy; eosinophil; Epidemic; Etiology; Exhibits; experience; experimental study; Feasibility Studies; Frequencies; Gene Expression; Glycosaminoglycans; Goblet Cells; Guidelines; Health Expenditures; Healthcare; Heparin; Histologic; Human; Hyperplasia; IgE; Immune; Impairment; improved; Individual; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-13; Interleukin-4; Interleukin-5; Intranasal Administration; Investigational New Drug Application; Irrigation; Lead; Measures; Mediating; Medical; mepolizumab; Microbial Biofilms; mouse model; Mucins; Mucociliary Clearance; Mucolytics; Mucous body substance; Mus; Nose; novel; novel therapeutics; Operative Surgical Procedures; Oral; pathogen; Pathogenesis; pathogenic bacteria; Patients; Penetration; Phase; Phenotype; Polyps; Population; pre-clinical; Predisposition; Prevalence; Production; Productivity; Property; Quality of life; Regimen; Research; response; Risk; Route; Safety; Saline; Serum; Signal Transduction; Sinus; statistics; Steroids; T-Lymphocyte; Testing; Therapeutic; TimeLine; tissue biomarkers; Tissues; TLR2 gene; Topical application; Treatment Efficacy; United States Food and Drug Administration