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Scalable Prime Editor Evolution for Correction of Inherited Retinal Diseases

Award Number: F32EY037536
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 09/29/2027

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Scalable Prime Editor Evolution for Correction of Inherited Retinal Diseases - PROJECT SUMMARY The gene-editing revolution is underway. However, early gene-editing technologies based on programmable nucleases, such as CRISPR-Cas9, are limited in editing scope and cause double-stranded breaks, leading to undesirable outcomes. Precision genome-editing technologies, such as prime editing, address these issues but are often insufficiently effective at editing clinically relevant loci. It is well established that variability in prime editor efficiency is influenced by target sequence and edit type. We hypothesize that prime-editor variants can be generated that edit different clinically relevant targets more efficiently through protein alterations. Doing so would require a scalable prime-editor evolution approach with sequence flexibility that would enable the targeting of numerous therapeutically relevant gene sequences. No report has presented this achievement on a large scale across multiple user-defined sequence targets. In this proposal, I describe a continuous biomolecular evolution system in yeast based on orthogonal DNA replication (OrthoRep), developed by my Sponsor, Prof. Chang Liu. I will leverage my recently developed approach, supported by preliminary results, that overcomes the limitation to scalable application of the OrthoRep system to genome editors, thereby facilitating the transfer of hypermutating linear plasmids from edited to unedited cells with high efficiency. I propose to conduct a large-scale evolution campaign on prime editors directed toward clinically relevant targets. With the statistical power derived from a high number of replicates per unique target, we will gain insights into the molecular mechanisms behind prime-editor improvements, sequence and edit-type specialization, as well as the general translatability of prime editors evolved in yeast to mammalian-cell editing. Enabled by my unique training environment that bridges the University of California, Irvine School of Engineering and the School of Medicine, our large-scale evolution campaign includes evolution of prime editors to exactly target key DNA sites, including a frameshift mutation in the MERTK gene and a missense mutation in the C1QTNF5 gene, known to cause inherited retinal disorders in clinical settings and model mice. This training plan and project encompass two primary phases. Training Phase 1 (TP1) includes modern biomedical engineering and evolution in the most genetically tractable eukaryotic model organism, the yeast Saccharomyces cerevisiae, and directed evolution in mammalian tissue culture in Prof. Liu’s primary laboratory space. In Training Phase 2 (TP2), translation will extend to mouse models of retinal degeneration by hands-on collaboration with expert clinician scientists at Prof. Palczewski’s vivarium space. The successful implementation of this training plan will provide experience throughout the full vertical pipeline of modern gene editing research. Successful implementation of this project will resolve questions about the translation of prime editors from yeast to editing in mammalian-cell tissue culture to editing in the murine retina in vivo.


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 = $79,480 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	1	4/3/2026	NEW	$79,480
														Subtotal = $79,480

Grand Total All Awards = $79,480

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Scalable Prime Editor Evolution for Correction of Inherited Retinal Diseases

Award Number: F32EY037536

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 09/29/2027

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