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Insulin-accelerated surgical approach to pre-retinal gene therapy

Award Number: K08EY036957
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/22/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Insulin-accelerated surgical approach to pre-retinal gene therapy - Project Summary/Abstract Inherited retinal disease (IRD) represents a molecularly heterogenous group of chronic blinding conditions that impact 5.5 million people worldwide, stemming from mutations in over 240 genes. The retina spans from the anterior barrier of inner limiting membrane (ILM) to the light-sensing photoreceptors posteriorly. The retina is positioned immediately anterior to the retinal pigment epithelium (RPE), which is critical for recycling the light- sensitive opsins in the apposed retinal photoreceptors as well as for paracrine support. Recently, the RPE has been elegantly shown to produce insulin locally, nearby the retina, which itself is rich in insulin receptors. Voretigene neparvovec (Luxturna) was the first FDA approved gene therapy for IRD treatment, treating patients with homozygous mutations in RPE65, but constituting just 0.5% of IRD patients. It works by introducing a functioning copy of RPE65 with an adeno-associated virus (AAV) injection under the retina. This creates a temporary retinal detachment but penetrates the anterior ILM barrier and focusses gene transduction in the RPE, where RPE65 primarily functions. Despite its initial success, considerable doubts remain in the field as many patients are challenged by ongoing chronic retinal/RPE atrophy in the area of subretinal bleb formation for AAV administration, causing subsequent treatment failure after initial success. Two proposed failure mechanisms include (1) immune response to residual vector, and (2) physical shearing forces on diseased and delicate photoreceptors during retinal detachment creation with subretinal delivery of AAV. Thus, the aims of the enclosed grant are constructed to test a novel AAV administration approach that combines both a pre- retinal (rather than subretinal) approach with adjuvant insulin administration to accelerate uptake of AAV into retinal cells. In this way, we propose that AAV uptake into retinal cells can be accelerated to the order of minutes, allowing for removal of residual AAV after transduction during surgery, avoidance of intentional retinal detachment, and prevention of inflammation from residual AAV. If successful, this gene agnostic approach could be quickly adopted to treat virtually any inherited retinal disease, and extended to nonviral approaches for larger genes. These studies will be carried out with strong support of the Ohio State Gene Therapy Institute and Department of Ophthalmology. The two lead mentors are R01 holding experienced principal investigators, with decades of experience directing laboratories that focus on retinal cell biology and central nervous system gene therapy, respectively. They have each successfully mentored multiple junior faculty members to R01 NIH funding. With their targeted mentorship and that of a separate Advisory Team, as well as educational coursework and intentional integration into the scientific community, support from this K08 will help transition Dr. Mendel from retinal cell biologist and surgeon to expert retinal gene therapy investigator.


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 = $206,739 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Vision Research	001	2	8/27/2026	NON-COMPETING CONTINUATION	$206,739
2026	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Vision Research	000	1	1/29/2026	NEW	$0
														Subtotal = $206,739

Issue Date FY: 2025 ( Subtotal = $206,739 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Vision Research	000	1	9/22/2025	NEW	$206,739
														Subtotal = $206,739

Grand Total All Awards = $413,478

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Insulin-accelerated surgical approach to pre-retinal gene therapy

Award Number: K08EY036957

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/22/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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