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Gene Editing for DFNA9 Deafness

Award Number: F32DC019839
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/06/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Gene Editing for DFNA9 Deafness - PROJECT SUMMARY/ABSTRACT Significant advances in gene discovery in the field of hearing and deafness have raised a great interest in developing new therapeutic approaches for genetic deafness. Hearing loss (HL), is the most common sensory deficit worldwide, affecting the quality of life of people of all ages. Despite the progress in the understanding of genetic etiologies and the molecular mechanisms involved in deafness, no effective therapies in restoring the natural hearing are as yet available. Given the massive burden posed by hearing problems and the emerging landscape of gene editing technology, it is now essential to address the unmet medical need and to pursue new strategies for treatment of inherited hearing loss. Recent reports of preclinical studies for developing targeted therapeutic approaches for inherited deafness have opened promising avenues for precision medicine in hearing loss. Recent reports have yielded encouraging results in preclinical trials of virally mediated gene therapy for inherited deafness. One disorder of interest is DFNA9, an autosomal dominant nonsyndromic late-onset HL with variable vestibular dysfunction, caused by mutations in COCH, encoding cochlin, the most abundantly detected protein in the inner ear. This disease model is similar to and representative of the majority of the genetic HL disorders with a dominant mode of inheritance with an underlying deleterious gain-of-function/dominant-negative mechanism of the mutant protein. The goal of this project is to develop a gene therapy strategy to treat hearing loss associated with DFNA9, along with training of a research fellow in the fields of human genetics of deafness. To achieve these goals, we plan to utilize state-of-the-art CRISPR-Cas9 gene editing technology to develop an allele-specific targeting approach, and to test its efficacy in halting or mitigating the development or progression of hearing loss in a knock-in (KI) mouse model of DFNA9 associated with the dominant COCH p.A449T mutation. Preliminary in vitro studies support the specificity of the developed CRISPR-Cas9 reagents and strategies. Furthermore, additional very recent phenotypic characterization of our novel Coch A449T KI mouse model at eight to nine months is consistent with late-onset hearing loss. We plan to perform more in-depth phenotyping of the Coch A449T KI mouse model, and to explore the mechanism of pathogenicity. We further plan to evaluate the efficiency and specificity of in vivo CRISPR-Cas9 target gene disruption in prevention or mitigation of progressive hearing loss. Carrying out the project aims will provide substantial progress in development of the essential steps required for translation of gene therapy into clinical application. This project will establish a knowledgeable research fellow in the field of hereditary deafness and gene therapy, who plans to lead research in precision medicine for hearing loss.


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: 2024 ( Subtotal = -$11,579 )
2024	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	2	10/31/2023	NON-COMPETING CONTINUATION	-$11,579
														Subtotal = -$11,579

Issue Date FY: 2023 ( Subtotal = $13,235 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	2	11/18/2022	NON-COMPETING CONTINUATION	$13,235
														Subtotal = $13,235

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	1	3/2/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $79,642 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	001	1	8/11/2021	NEW	$0
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Research Related to Deafness and Communication Disorders	000	1	8/11/2021	NEW	$79,642
														Subtotal = $79,642

Grand Total All Awards = $81,298

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Gene Editing for DFNA9 Deafness

Award Number: F32DC019839

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/06/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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