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Precise genome editing in the zebrafish

Award Number: R01GM165452
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/25/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Precise genome editing in the zebrafish - SUMMARY This proposal addresses the most pressing deficiency restricting research utilizing the zebrafish: the limited ability to edit the zebrafish genome precisely. Current technology aimed at modifying or replacing selected spans of sequence or intended to accurately insert foreign sequences at any selected site is so inefficient that, in practice, using the zebrafish to generate disease models or test the functions of human variants is daunting and prohibitive. New methods to readily and accurately alter/replace genome sequences would revolutionize use of the zebrafish for both basic and applied purposes, profoundly impacting a significant and broad biomedical research community. We have developed a new easy-to-implement method that improves the efficiency of precise base substitution editing in the zebrafish about 20-fold. We use single strand DNA donors to direct homology-directed repair stimulated by nicks induced by a nickase version of Cas9, Cas9D10A. Alleles containing 50-76bp stretches of perfectly edited sequence are routinely transmitted by ~10% of adult F0’s. The edited alleles we recover are present as 1/8-1/3 of the gametes of the F0 germ line. As a result, for the first time, new alleles identifiable only by detection of DNA sequence modifications can be recovered with ease. In response to PAR-25-203, this proposal focuses solely on advancing our methods for precise editing of the zebrafish genome to the stage where it is fully portable and can be readily implemented by any investigator. In Aim 1 we further improve and optimize the efficiency with which precise base substitution edits can generated, and then we establish the method, fully characterizing the parameters and limitations of its implementation, so investigators know how best to design experiments. In Aim 2 we validate the method by producing edited alleles at multiple loci, including essential genes. We illustrate the potential of the technology for biomedical research by generating alleles that will be used to address a broad range of questions related to human disease, evolution, and the roles of predicted regulatory elements in gene regulation. The alleles will be used in future collaborations to probe these questions. In Aim 3, we address remaining hurdles, extending the technology so it can drive incorporation of blocks of sequence to effectively introduce epitope tags and reporter proteins. The project will have a transformative effect on the use of zebrafish to generate disease models, for uncovering disease processes and developing drug therapies. It will allow testing the function of any polymorphism that has been proposed to affect gene function or phenotype. It will support new exciting approaches study the roles and mechanisms of action of sequences that regulate gene expression.


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 = $556,000 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	000	1	8/25/2026	NEW	$556,000
														Subtotal = $556,000

Grand Total All Awards = $556,000

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Precise genome editing in the zebrafish

Award Number: R01GM165452

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/25/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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