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In-silico screen and in-vivo evaluation of FDA-approved drugs to treat noise-induced hearing loss

Award Number: R21DC022085
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: 09/11/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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In-silico screen and in-vivo evaluation of FDA-approved drugs to treat noise-induced hearing loss - Acquired hearing loss is a major public health concern, affecting quality of life and leading to social isolation, depression, and cognitive decline. Roughly one-third of all acquired hearing loss cases are attributed to noise- induced hearing loss, a prevalent occupational injury. Current interventions, such as hearing aids and cochlear implants, provide limited relief and are imperfect solutions. The mammalian inner ear sensory hair cells, spiral ganglion neurons, and cells of the stria vascularis are particularly vulnerable to irreversible damage and do not regenerate upon injury, making noise-induced or age- related cellular loss permanent. They are highly metabolically active and rich in mitochondria. Hence, mitochondrial dysfunction is a leading cause of several forms of deafness. As in many other cell types, cochlear mitochondria are responsible for vital functions, including energy production, cell signaling, calcium (Ca2+) buffering, and apoptosis. These functions are dependent on mitochondrial Ca2+ entering through the multi-protein Mitochondrial Calcium Uniporter (MCU) complex, whose human atomic structure is solved and known. MCU contributes to rapid mitoCa2+ buffering, ensuring cytosolic Ca2+ homeostasis. Previous studies report that acoustic overstimulation causes elevated cytoplasmic Ca2+ levels in hair cells, leading to mitochondrial Ca2+ overloading. Inhibition of MCU activity using genetic manipulation to knock-out MCU components or systemic application of a MCU inhibitor reduced noise-induced auditory threshold shifts and prevented the loss of hair cells and synaptic ribbons. We hypothesize that MCU can be targeted pharmacologically to prevent noise- induced hearing loss. By modulating MCU activity through repurposing FDA-approved drugs, we aim to expedite the development of novel treatments to mitigate cochlear damage and maintain hearing function following noise insult. Our comprehensive approach involves in silico screening to identify MCU modulators, with subsequent in vitro, ex vivo, and in vivo evaluations of candidate compounds for safety and efficacy to repurpose FDA-approved compounds as otoprotective drugs. The top candidate drug will be delivered to mice trans-tympanically immediately after noise trauma and tested for their ability to prevent noise-induced hearing loss. The cochlear structure and function will be evaluated at various time points during recovery with well-established techniques. In summary, our study aims to identify FDA-approved drugs capable of reversibly blocking mitochondrial Ca2+ uptake to prevent noise-induced damage that mitochondria-rich cochlear cells undergo following noise insult. Reversible modulators will ensure the effect is temporary and relevant only during the critical recovery period immediately following noise trauma. Unlike typical slow and expensive de novo drug discoveries, repurposing FDA-approved drugs offers a cost- and time-efficient alternative for discovering novel therapies.


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 = $473,749 )
2025	2025	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	1	9/11/2025	NEW	$473,749
														Subtotal = $473,749

Grand Total All Awards = $473,749

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In-silico screen and in-vivo evaluation of FDA-approved drugs to treat noise-induced hearing loss

Award Number: R21DC022085

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: 09/11/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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