SBIR-STTR Award

?The purpose of the research being proposed is to develop a highly effective nasal rinse that can treat chronic rhinosinusitis (CRS) in an entirely new way. Often CRS is overlooked because it is rarely life- threatening. CRS is estimated to affect an astounding 13% of the US population with direct costs exceeding $8 billion annually, and additionally causing 73 million limited activity days according to the 1992 CDC Vital and Health Statistics report. Coupling said impact with a lack of effective therapies creates a strong opportunity to address a major unmet need in the market. Many individuals suffering from CRS exhibit decrease nitric oxide (NO) concentrations in their sinus cavities. NO is a potent and natural antimicrobial molecule that healthy individuals produce at high levels in their sinuses. NOTA Laboratories, LLC, has identified safe and naturally occurring therapeutic agents that can enhance the levels of NO in the sinus airways. NO has been proven to stimulate mucociliary clearance and reduces microbial biofilm formation. Dr. Meyerhoff's laboratory at the University of Michigan has spent >15 years studying the biomedical applications of NO releasing agents/materials and has worked with several outside parties to harness the therapeutic properties of NO in the healthcare space. NOTA Laboratories' team of researchers, chemists, pulmonologists, and otolaryngologists believes in this innovative therapy, and has the expertise to further its development to treat/prevent CRS. Using funding from this NIH STTR, the company plans to 1) identify and optimize a formulation that incorporates S-nitrosoglutathione (GSNO) along with additives within typical saline sinus rinse solutions and examine the rates of NO release at room temperature and 37 oC using chemiluminescence measurements; and 2) test the ability of such NO-releasing solutions to disrupt bacterial biofilm, kill biofilm bacteriaand increase ciliary beat frequency in vitro using biofilms established on mucociliary- differentiated primary sinus epithelial cell cultures. The results will drive Phase II studies where NOTA will tes the optimal nasal rinse formulations derived from this Phase I study in suitable animal models as a prelude to clinical trials in collaboration with a research team at the University of Michigan Medical School.

Public Health Relevance Statement:


Public Health Relevance:
Chronic rhinosinusitis (CRS) affects an estimated 13% of the US population, with direct costs exceeding $8 billion annually. Because currently marketed therapies are of limited effectiveness, this unmet need represents an immense commercial opportunity. Research has shown that CRS patients have reduced nitric oxide (NO) levels in their sinus cavities and this likely contributes to formation of S. aureus and other microbial biofilms that cannot be effectively eradicated by antibiotics. Through the research described in this application, NOTA Laboratories will develop an inexpensive but effective topical sinonasal spray or rinse solution product containing S-nitrosoglutathione (GSNO), an endogenous carrier of NO in humans, to increase levels of NO in the sinus cavities of CRS patients and thereby treat/prevent CRS in a large number of patients.

NIH Spending Category:
Allergic Rhinitis (Hay Fever); Clinical Research; Emerging Infectious Diseases; Infectious Diseases; Prevention

Project Terms:
Address; Adult; Aerosols; Affect; Amber; Animal Model; Antibiotics; antimicrobial; antimicrobial drug; Ascorbic Acid; Bacteria; base; Blood; Cell Culture Techniques; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemiluminescence assay; chronic rhinosinusitis; Clinical Trials; Collaborations; cost; Coupled; Coupling; Cysteine; density; Detection; Development; Devices; digital; Direct Costs; Disease; Drug Formulations; economic impact; Edetic Acid; effective therapy; Effectiveness; Epithelial Cells; Exhalation; Exhibits; Flushing; Frequencies (time pattern); Funding; Gentian Violet; Glutathione; Health; Healthcare; Hour; Human; IL8 gene; Immune; Immunofluorescence Immunologic; improved; In Vitro; Individual; Inflammatory Response; Innovative Therapy; Ions; Irrigation; Killings; Laboratories; Life; Marketing; Measures; medical schools; Methods; Michigan; microbial; Microbial Biofilms; microorganism; Microscope; Mucociliary Clearance; Mucous body substance; Mucous Membrane; Nasal cavity; natural antimicrobial; Nitric Oxide; Nose; Organism; Otolaryngologist; Patients; Pharmaceutical Preparations; Phase; phase 1 study; phase 2 study; Population; Powder dose form; prevent; Prevention; productivity loss; Property; Pseudomonas aeruginosa; public health relevance; Reagent; reconstitution; Reporting; Research; Research Personnel; rhinosinusitis; Risk; S-Nitrosoglutathione; S-Nitrosothiols; Saline; Selenocysteine; Sinus; Small Business Technology Transfer Research; Sodium Bicarbonate; Solutions; Specialist; Speed (motion); Staining method; Stains; Staphylococcus aureus; statistics; Surface; Tablets; Technology; Temperature; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Trace metal; United States; United States National Institutes of Health; Universities; Vial device; Visit; Water; Work

Chronic rhinosinusitis (CRS) is estimated to affect 13% of the US population, with annual health care direct costs of nearly $10 billion per year, yet there are few effective therapies for CRS. Detection of Staphylococcus aureus and/or Pseudomonas aeruginosa biofilm in the sinus mucosa is associated with severe CRS presentation. Healthy cells that line the nasal passages normally emit significant levels of nitric oxide (NO), a potent and natural antimicrobial molecule that stimulates mucociliary clearance and reduces bacterial biofilm formation. Reduced levels of NO in the exhaled nasal breath of CRS patients suggest that boosting local NO concentrations within the sinuses may be quite beneficial. In Phase I of this project, NOTA Laboratories, LLC, clearly demonstrated that a naturally occurring and inexpensive NO releasing agent, S-nitrosoglutathione (GSNO), can be incorporated into a typical saline/bicarbonate sinus rinse solution and generate adequate levels of NO to significantly reduce levels of live bacteria counts for two biofilm forming CRS microbes (S. aureus and P. aeruginosa). In these experiments, the bacterial biofilms were grown on the surface of human upper airway epithelial cells. We further demonstrated that the levels of GSNO and concomitant NO released do not harm the underlying human cells, as assessed by monitoring the levels of a toxicity-associated cytokine (IL-8). In addition, NOTA demonstrated that the release rates of NO from GSNO can be enhanced by the presence of ascorbate (Asc; vitamin C) and that the resulting powder formulations of GSNO/Asc can be stored for more than 6 months (at 37 °C) while retaining >80% of their NO release capability. Via Phase II SBIR funding, NOTA will: 1) Further optimize the concentration of the GSNO/Asc mixture within an isotonic NaCl/NaHCO3/EDTA solution and frequency of application for the in vitro disruption of S. aureus and P. aeruginosa biofilms formed on human upper airway epithelial cells over 3 d test periods; 2) Explore a commercial packaging process (in polymer film lined aluminum pouches) and test the resulting 1-year stability of a dry packaged GSNO/Asc/NaCl/NaHCO3/EDTA mixed powder that will be reconstituted in plastic sinus flush bottles with 240 mL of pure water immediately before use by patients; 3) Conduct animal studies in rabbits to determine if NOTA's reconstituted RSNO/Asc/NaCl/NaHCO3/EDTA formulation, given as an aerosol spray twice daily over a 7 d period, significantly decreases bacterial counts in the sinus cavities of infected rabbits (with CRS) vs. controls (only NaCl/NaHCO3/EDTA); and 4) Begin the regulatory process by obtaining expert assessments of the role of the FDA in approval of the new GSNO formulations as a potential over-the-counter product for the CRS market. The completion of these efforts during Phase II will enable NOTA to plan the first human subject clinical trials at the University of Michigan Sinus Center as part of Phase III studies.

Public Health Relevance Statement:
NARRATIVE Chronic rhinosinusitis (CRS) affects an estimated 13% of the US population, with direct costs of nearly $10 billion annually. The inadequacy of current therapies presents an unmet need of immense commercial opportunity. CRS patients are known to have reduced nitric oxide (NO) levels in their sinus cavities, which contribute to the formation of microbial biofilm that cannot be eradicated by antibiotics. Phase 1 research has demonstrated the effectiveness of NOTA Laboratories' new sinonasal spray/rinse solution containing S-nitrosoglutathione (GSNO) that releases low levels of NO capable of reducing microbial biofilm grown on the surface of human epithelial cells without exhibiting any toxicity toward the human cells. In Phase II, further development of this product is proposed, including additional optimization of a dry powder formulation, commercial packaging studies, animal experiments, and exploring the regulatory issues required for the eventual launch of a new product that will have a profound impact on the prevention/treatment of CRS for many patients. !

Project Terms:
Adult; Aerosols; Affect; Aluminum; Animal Experiments; Animals; Antibiotics; antimicrobial; antimicrobial drug; Antimicrobial Effect; Antiviral Agents; ascorbate; Ascorbic Acid; Bacteria; Bacterial Counts; base; Bicarbonates; Blood; Blood Circulation; Cell Line; Cells; chronic rhinosinusitis; Clinical Trials; Common Cold; cost; cytokine; Data; Detection; Direct Costs; Disease; Dose; economic impact; Edetic Acid; effective therapy; Effectiveness; Epithelial Cells; Exhalation; Exhibits; experimental study; Expert Opinion; Film; Flushing; Formulation; Frequencies; Funding; Generations; Glutathione; Healthcare; Histologic; Hour; Human; human subject; IL8 gene; improved; In Vitro; in vivo; Individual; innovative technologies; Isotonic Exercise; Laboratories; Laboratory Animal Medicine; Literature; Measures; Michigan; Microbe; microbial; Microbial Biofilms; Modeling; Monitor; Mucociliary Clearance; Mucous Membrane; natural antimicrobial; Nitric Oxide; Nose; Oryctolagus cuniculus; Patients; Pennsylvania; Pharmaceutical Preparations; Phase; phase 1 study; phase 3 study; Plasticizers; Polymers; Population; Powder dose form; pre-clinical; prevent; Prevention; Process; product development; Productivity; Pseudomonas aeruginosa; reconstitution; Reducing Agents; Research; rhinosinusitis; Risk; Role; S-Nitrosoglutathione; S-Nitrosothiols; Saline; Sinus; Small Business Innovation Research Grant; Specialist; Staphylococcus aureus; Surface; Technology; Test Result; Testing; Time; Toxic effect; treatment duration; Universities; Visit; Water