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S-Nitrosothiol-Based Rinse/Aerosol Solutions for Treatment/Prevention of Rhinosinusitis (Phase II)

Award Number: R44AI120443
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract: 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2018	NOTA LABORATORIES LLC	600 S WAGNER RD	ANN ARBOR	MI	48103	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	3	12/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	NOTA LABORATORIES LLC	600 SOUTH WAGNER ROAD, SUITE 6	ANN ARBOR	MI	48103	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	3	6/5/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $651,685 )
2018	2018	NOTA LABORATORIES LLC	600 SOUTH WAGNER ROAD, SUITE 6	ANN ARBOR	MI	48103	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	3	7/27/2018	NON-COMPETING CONTINUATION	$646,507
2018	2017	NOTA LABORATORIES LLC	600 SOUTH WAGNER ROAD, SUITE 6	ANN ARBOR	MI	48103	WASHTENAW	USA	Allergy and Infectious Diseases Research	002	2	9/20/2018	COMPETING CONTINUATION	-$45,537
2018	2017	NOTA LABORATORIES LLC	600 SOUTH WAGNER ROAD, SUITE 6	ANN ARBOR	MI	48103	WASHTENAW	USA	Allergy and Infectious Diseases Research	001	2	8/13/2018	COMPETING CONTINUATION	$50,715
														Subtotal = $651,685

Issue Date FY: 2017 ( Subtotal = $858,200 )
2017	2017	NOTA LABORATORIES LLC	600 SOUTH WAGNER ROAD, SUITE 6	ANN ARBOR	MI	48103	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	2	8/11/2017	COMPETING CONTINUATION	$858,200
														Subtotal = $858,200

Grand Total All Awards = $1,509,885

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S-Nitrosothiol-Based Rinse/Aerosol Solutions for Treatment/Prevention of Rhinosinusitis (Phase II)

Award Number: R44AI120443

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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