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Preclinical evaluation of a homing endonuclease gene therapy for adRP in models of P23H retinopathy.

Award Number: R01EY032645
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Preclinical evaluation of a homing endonuclease gene therapy for adRP in models of P23H retinopathy. - Autosomal dominant Retinitis pigmentosa (adRP) is a blinding eye disease that results in loss of rods and eventually cone photoreceptors. A large fraction of adRP is caused by mutations in the rhodopsin (Rho) gene, and the most common mutation in North America causes a P23H mutation in rhodopsin. Patients typically present with mid- to late-stage disease when many rod photoreceptors already have degenerated. We will evaluate genome editing using a meganuclease genome editing tool (Rho1-2) that is specific for the sequence causing the P23H mutation in several preclinical animal models of P23H adRP. We will deliver AAV5- GRK1-Rho1-2 via subretinal injection to infect photoreceptors. We will measure efficacy, the ability of Rho1-2 to alter rod degeneration and functional decline. We will quantitatively determine Rho1-2 efficiency, the proportion of P23H alleles with insertions/delections (indels), specificity the proportion of P23H to WT alleles with indels, and its safety, the absence of indels in other genes throughout the human genome (off target editing). In Pig P23H adRP models we will evaluate Rho1-2 editing efficacy because of the similarities between pigs and humans in eye size and retinal structure and because the pig has a cone rich visual streak. We will use the same non-invasive tools used in the clinic to measure retinal function (full field electroretinograms) and structure, (spectral domain OCT). We will use two existing transgenic pig lines that harbor the entire P23H hRHO gene, but differ in their time course, resulting in a fast or slow loss of rods and rod function. We will match treatment time with the natural history of rod structural and functional decline, compare Rho1-2 editing efficacy in early-, mid- and late-stage P23H adRP and define its temporal treatment window. In Humanized adRP mouse models we will evaluate Rho1-2 editing efficiency and specificity because they contain WT and P23H human alleles in the appropriate genomic context. In human retinal organoids we will evaluate Rho1-2 editing safety (off-target cutting throughout the genome) because they contain human photoreceptors as well as the rest of the human genome in a relevant context.. Taken together the results of our experiments will determine if Rho1-2 should move forward for eventual use in human clinical trials and will define endpoints for those trials.


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 = $574,292 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	000	3	4/30/2025	NON-COMPETING CONTINUATION	$574,292
														Subtotal = $574,292

Issue Date FY: 2024 ( Subtotal = $568,819 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	000	2	3/11/2024	NON-COMPETING CONTINUATION	$568,819
														Subtotal = $568,819

Issue Date FY: 2023 ( Subtotal = $523,726 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	000	1	2/28/2023	NEW	$523,726
														Subtotal = $523,726

Grand Total All Awards = $1,666,837

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Preclinical evaluation of a homing endonuclease gene therapy for adRP in models of P23H retinopathy.

Award Number: R01EY032645

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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