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

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $694,739

## Abstract

ABSTRACT
This is a competitive renewal of R01EY024280, “Developing Efficient AAV Vectors for Photoreceptor Targeting
via the Vitreous”. Note that, due to advances made during the initial funding period, and our improved
understanding of challenges in the field, our title has been changed to “Engineering AAV for safe and efficient
gene delivery to the human retina” to more broadly encompass our goals. 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, injection of vector under the fovea of some patients led to central retinal
thinning and loss of visual acuity. Similar decreases in retinal thickness were also observed in Choroideremia
clinical trials. In more severe conditions, like X-linked Retinoschisis (XLRS), there is concern that subretinal
injection (SRI) will further damage patient retinas. Since most inherited retinal diseases (IRDs) are caused by
mutations in photoreceptor (PR)- and retinal pigment epithelial (RPE)- specific genes, development of gene
therapies that more safely and efficiently target these cells remains a significant, unmet need. Targeting foveal
cones is especially important, as they are responsible for acute, daylight vision. During the initial funding period,
we developed AAV capsids capable of efficient retinal transduction following intravitreal injection (IVI) in primate.
The inner limiting membrane (ILM) is the major barrier to AAV transduction via this this route. However, results
from clinical trials utilizing IVI AAVs that show dose-limiting inflammation, and neutralization of the AAV capsid
by pre-existing antibodies (NAbs) implicate the host immune system as a more immediate ‘barrier’ to clinical
translation. The eye’s ‘immune-privilege’ has perhaps led to an under appreciation of the immune system’s role
in shaping the outcome of intra-ocularly delivered AAVs. Naturally occurring antibodies to capsids capable of
transducing retina via the vitreous (i.e. AAV2) are prevalent in up to 70% of humans. As such, a large percentage
of patients will not meet inclusion criteria for emerging therapies. Here we propose experiments, based on strong
preliminary data, to overcome these barriers. The majority of work will be performed in primates (macaque) as
these barriers can only be recapitulated in intact eyes of animals with ocular characteristics and immune systems
similar to humans. In Aim 1, we will enhance transduction and safety of intravitreally delivered AAVs by
engineering the capsid and genome to avoid immune recognition. In Aim 2, we will enhance retinal transduction
by subILM delivery of AAVs to enable efficient and specific transduction of inner and outer retina. In Aim 3, we
will enhance transduction by subretinally delivered AAVs that spread laterally beyond the injection site. Vectors
and methods investigated in this proposal will have an immediate impact on planned clinical t...

## Key facts

- **NIH application ID:** 10004652
- **Project number:** 5R01EY024280-07
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Shannon Elizabeth Boye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $694,739
- **Award type:** 5
- **Project period:** 2014-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004652

## Citation

> US National Institutes of Health, RePORTER application 10004652, Engineering AAV for safe and efficient gene delivery to the human retina (5R01EY024280-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10004652. Licensed CC0.

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