# Retinal-adhesive thermoresponsive gel for AAV-mediated gene delivery to the outer retina

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $722,637

## Abstract

Project summary
Until recently, there have been no effective treatments for retinal degenerations. FDA approval of Luxturna, the
first gene therapy for bi-allelic mutations in RPE65, has opened the field for application to a broader range of
retinal diseases. The rapidly growing number of clinical trials and emerging companies reflect the impact of this
success and indicate the high expectations for retinal gene therapy. However, there is a significant need to
develop new approaches for the many remaining forms of retinal degenerations, as RPE65-related dystrophies
affect a very small population of patients. Moreover, the combination of the vector and surgical approach used
for this disease is suboptimal for targeting the fovea in retinas with significant structural alterations. The major
obstacles that must be addressed to improve clinical outcomes and extend the application of gene therapies to
numerous retinopathies at various disease stages are: 1) efficient vector delivery to the central retina without
damaging remaining photoreceptors, a significant, documented concern with sub-retinal injections in conditions
where the retina is structurally compromised, 2) efficiently targeting gene delivery to affected cells, especially
photoreceptors and RPE across the retina and 3) limiting the inflammatory/immune responses associated with
intravitreal injections. These issues are relevant to all current and future retinal gene therapy programs. Here,
we address each of these obstacles through development of an innovative new epiretinal gene therapy approach
for NPHP5-LCA and RPE65-LCA2, in which a novel, biocompatible, retinal adhesive gel developed by our team
releases high efficiency AAVs directly to the retina. We have created a comprehensive and efficient development
plan that allows for rapid translation, drawing on the complementary skill sets of a team of experts with a track
record of successful translational development. We will further develop the tunable, biocompatible gel and
injection system to deliver these vectors directly to the retina, and we will incorporate a backing layer into the
implant that allows for directionality of vector release for increased efficiency. We will determine the most efficient
implant-compatible photoreceptor and RPE-targeting AAV vectors by utilizing our recently developed single cell
RNA-Seq paradigm. We will fully validate this new gene therapy platform in two well-studied naturally occurring
canine models of LCA that affect primarily the photoreceptors (NPHP5-LCA) and RPE (RPE65-LCA2), and we
will characterize immune response and toxicity. The innovative approach developed herein will result in a new
platform for direct, non-invasive and efficient AAV delivery to the retina, reducing diffusion and required dosage
as well as the related immune response. This novel gene delivery platform has direct applicability to all outer
retinal disease targets, paving the way forward for a safer, more efficient and targ...

## Key facts

- **NIH application ID:** 10898763
- **Project number:** 5R01EY033049-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** William A. Beltran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $722,637
- **Award type:** 5
- **Project period:** 2022-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898763

## Citation

> US National Institutes of Health, RePORTER application 10898763, Retinal-adhesive thermoresponsive gel for AAV-mediated gene delivery to the outer retina (5R01EY033049-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10898763. Licensed CC0.

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