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Determining the ototoxic potential of COVID-19 therapeutics using machine learning and in vivo approaches

Award Number: R01DC020701
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/07/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Determining the ototoxic potential of COVID-19 therapeutics using machine learning and in vivo approaches - Project Summary/Abstract There are over 900 drugs and drug combinations currently in clinical trials for COVID-19. While this pace of drug development is necessary, it also comes with increased risk of producing therapies with significant side- effects. One likely side-effect of some COVID-19 drugs is hearing loss. The potential of drugs to cause hearing loss is typically unassessed during drug development or clinical testing. Our research will rapidly assess COVID-19 drugs for ototoxic potential, as per NOT-DC-20-008 to determine the “Potential ototoxicity from therapeutics or vaccination related to COVID-19.” Our goal is to promote the development of safe COVID-19 drugs with minimal side effects. Some drugs in clinical trials for COVID-19 are associated with hearing loss but the ototoxic potential for these drugs is based on individual case reports or in vitro experiments so the true ototoxic burden is largely unknown. We should not use patients as a testbed for a life-altering negative side- effect when there are rapid low-cost alternatives available. The objective of this proposal is to rapidly identify the ototoxic potential of COVID-19 therapeutics using both in silico and in vivo approaches. We will achieve this objective with three Specific Aims: 1) Predict ototoxic potential of COVID-19 therapies with Machine Learning (ML), 2) Determine the relative hair cell toxicity of COVID-19 therapies in the zebrafish lateral line, and 3) Determine the degree to which predicted ototoxins cause hearing loss in rats. Our innovative ML model correctly categorizes ototoxins vs. non-ototoxins with 87% accuracy. In this project we will employ our current model for immediate ototoxicity detection and further optimize the model for better predictive accuracy. In parallel with the ML model, we will screen COVID-19 therapeutics in the larval zebrafish lateral line, which is an excellent model for rapid ototoxicity screening. Prior work by our group and others demonstrates the validity of the lateral line as a platform for effective ototoxin discovery. Finally, we will validate predicted ototoxins from Aims 1 and 2 in rats using both physiological and morphological assays. Our research is significant because we will determine the ototoxic potential of new or repurposed therapeutics for COVID-19, which can inform efforts to 1) advance effective candidates that are not ototoxic, 2) modify successful yet ototoxic COVID-19 drugs and/or develop otoprotective co-therapies to preserve therapeutic efficacy while minimizing ototoxic side- effects, and 3) determine which patients require audiometric monitoring due to the drugs they receive. Our team includes experts in ototoxicity, medicinal chemistry, biostatistics, machine learning, and clinical expertise in large-scale human trials for COVID-19 therapies. Our research is highly likely to identify ototoxic COVID-19 drugs, facilitating development of safer pharmacotherapies to combat this deadly pandemic. Further, many drugs in clinical trials for COVID-19 are already approved for other indications. Our research will therefore provide important data about drugs in clinical use for non-COVID-related disease, adding additional value.


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: 2025 ( Subtotal = -$26,142 )
2025	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	005	3	5/5/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$50
2025	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Research Related to Deafness and Communication Disorders	003	2	5/5/2025	NON-COMPETING CONTINUATION	-$34
2025	2024	CREIGHTON UNIVERSITY	2500 CALIFORNIA PLAZA	OMAHA	NE	68178	DOUGLAS	USA	Research Related to Deafness and Communication Disorders	002	3	3/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$255,266
2025	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Research Related to Deafness and Communication Disorders	000	2	3/19/2025	NON-COMPETING CONTINUATION	-$255,268
2025	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Research Related to Deafness and Communication Disorders	004	2	5/5/2025	SUPPLEMENT FOR EXPANSION	-$16
2025	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Research Related to Deafness and Communication Disorders	001	2	3/19/2025	SUPPLEMENT FOR EXPANSION	-$26,140
														Subtotal = -$26,142

Issue Date FY: 2024 ( Subtotal = $487,469 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Research Related to Deafness and Communication Disorders	002	2	8/1/2024	SUPPLEMENT FOR EXPANSION	$53,296
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Research Related to Deafness and Communication Disorders	000	1	3/7/2024	SUPPLEMENT FOR EXPANSION	$39,973
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Research Related to Deafness and Communication Disorders	001	2	5/17/2024	NON-COMPETING CONTINUATION	$394,200
														Subtotal = $487,469

Issue Date FY: 2023 ( Subtotal = $400,317 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Research Related to Deafness and Communication Disorders	000	1	6/7/2023	NEW	$400,317
														Subtotal = $400,317

Grand Total All Awards = $861,644

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Determining the ototoxic potential of COVID-19 therapeutics using machine learning and in vivo approaches

Award Number: R01DC020701

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/07/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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