# Engineering AAV for safe and efficient gene delivery to the human retina

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $651,115

## Abstract

ABSTRACT
This is a competitive renewal of R01EY024280, “Engineering AAV for safe and efficient gene delivery to the
human retina”. FDA approval of an Adeno associated virus (AAV)- based gene therapy for RPE65-Leber
congenital amaurosis (LCA2) solidified gene therapy’s place in current medical practice. However, in the 6 years
since, there have been no additional approvals, and multiple hurdles associated with retinal gene therapy have
come to light. The development of therapies that safely and efficiently target the human retina remains a
significant, unmet need. In previous funding cycles, we asked questions grounded in both basic and translational
science. We have i) elaborated upon biological determinants of retinal transduction by AAV via different routes
of administration, ii) identified novel variants with increased potency and neutralizing antibody evasion relative
to benchmark vectors and iii) identified a novel variant with the ability to spread laterally beyond the margins of
the subretinal injection bleb. Notably, we have also translated our findings- our laterally spreading capsid is being
used in an ongoing Phase I/II clinical trial to treat X-linked retinoschisis (NCT05878860). The scope of our
proposed studies is broadened based on the advances we’ve made, and our evolving understanding of
challenges in the field. A significant portion of the proposed work will be performed in macaques as these
challenges are most effectively modeled in intact eyes of animals with ocular characteristics and immune
systems most similar to humans. In Aim 1, we explore the biological determinants of retinal transduction by AAV.
We will use a novel in-situ visualization approach to analyze retinal glycans and their interactions with the AAV
capsid across species, evaluate the role of Müller glia in retinal transduction following intravitreal injection, and
determine the retinal distribution of ‘universal AAV’ host cell factors, AAVR and GPR108 and their roles in retinal
transduction via multiple routes of administration. In Aim 2, we will enhance transduction and safety of AAV
capsids delivered by intravitreal injection. Capitalizing on strong preliminary data, this Aim expands capsid library
screening to non-AAV2- based capsids. In Aim 3, we will enhance the biodistribution and safety of AAV capsids
delivered by subretinal injection. We propose to block capsid interactions with host cellular factors to limit
transduction of peripheral tissues and/or endogenous antigen presenting cells, while simultaneously enhancing
PR and/RPE transduction. Vectors and methods investigated in this proposal will have an immediate impact on
planned clinical trials to address inherited retinal diseases as well as non-orphan indications such as AMD.
Development of these tools by academia (rather than industry) will ensure the availability of shared resources
with the broader scientific community.

## Key facts

- **NIH application ID:** 10981267
- **Project number:** 2R01EY024280-11
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Shannon Elizabeth Boye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $651,115
- **Award type:** 2
- **Project period:** 2014-06-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981267

## Citation

> US National Institutes of Health, RePORTER application 10981267, Engineering AAV for safe and efficient gene delivery to the human retina (2R01EY024280-11). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10981267. Licensed CC0.

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