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AAV-mediated editing to treat human autosomal dominant hearing loss DFNA41 and DFNA2

Award Number: U01TR005352
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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AAV-mediated editing to treat human autosomal dominant hearing loss DFNA41 and DFNA2 - Project Summary/Abstract 1 in 500 newborns suffers from genetic hearing loss (HL), and there are no FDA-approved drugs or biological treatments for any type of HL. Genome editing that disrupts or repairs DNA mutations or modulates RNA levels is being developed into new therapies for many diseases. Despite the unprecedented progress, the translation of genome editing into therapy in humans has been challenging due to the obstacles in delivery, safety, and efficacy. This is particularly relevant for in vivo editing therapy due to the added complexity, including damped editing efficiency, inefficiency in reaching the target cells, and the lack of evidence of translatability from animal (mouse) into humans. In this proposal, we will develop first- in-class CRISPR-Cas-based therapeutics for genetic hearing loss by conducting IND-enabling studies of AAV2-mediated delivery of SaCas9-KKH/gRNA to target two dominant genetic hearing loss, DFNA41 due to a P2RX2 mutation and DFNA2 due to a KCNQ4 mutation. This project will be conducted by a consortium of five core teams with unique and complementary expertise and experience in gene and editing treatments for genetic hearing loss, from animal models to human trials, editing technology, and regulatory processes. We have recently conducted the first successful gene therapy of OTOF clinical trial by dual adeno-associated virus (AAV) that leads to hearing restoration in children with congenital genetic hearing loss DFNB9, which included a safety study of AAV in non-human primates (NHPs) and the development of a minimally invasive surgical procedure for AAV inner ear delivery in humans. We have further developed a large animal pig model of dominant genetic hearing loss DFNA36 by inserting a mutation into the TMC1 gene and successfully rescued hearing in the pig model by local AAV delivery of editing complex, demonstrating the cross-species translatability of editing therapy for genetic hearing loss. For the current proposal, we have obtained the therapeutic benefit of hearing rescue results by AAV2 delivery of SaCas9-KKH/gRNA to treat DFNA41 and DFNA2 mouse models, which lays the foundation of an IND-enabling study. Leveraging our unparalleled expertise and experience in human genetic hearing loss, including efficacious editing treatment in mouse and pig models, AAV safety study in NHP, and the first successful human gene therapy clinical trial, we will conduct the following studies: 1). Establish off-target editing profiles in human cells and human inner ear tissues; 2). Efficacy study by escalating doses of AAV2 in DFNA41 and DFNA2 mouse models; 3). Biodistribution and toxicity study in WT mice by an escalating dose of AAV2; 4). Biodistribution and toxicity study of GLP grade AAV2 in NHP; 5). Patient natural history study, and 6). Regulatory Interactions & IND completion. We have assembled a team of experts in each area with a project manager to execute the plan, develop a streamlined regulatory path for two types of DFNA deafness, and disseminate this regulatory information to the scientific community. Successful completion of the IND-enabling studies makes our approach applicable to over 20 dominant genetic hearing loss due to hair cell mutations.


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: 2026 ( Subtotal = $0 )
2026	2025	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Research Support	000	2	3/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $3,227,062 )
2025	2025	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Research Support	000	2	7/31/2025	NON-COMPETING CONTINUATION	$3,227,062
														Subtotal = $3,227,062

Issue Date FY: 2024 ( Subtotal = $3,314,560 )
2024	2024	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Research Support	000	1	9/20/2024	NEW	$3,314,560
														Subtotal = $3,314,560

Grand Total All Awards = $6,541,622

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AAV-mediated editing to treat human autosomal dominant hearing loss DFNA41 and DFNA2

Award Number: U01TR005352

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/20/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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