# AAV Induced Toxicity in the Eye

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $416,375

## Abstract

PROJECT SUMMARY / ABSTRACT
AAV vectors have emerged as the leading vector for gene delivery to multiple tissues, proving to be both safe
and efficacious in several clinical trials. However, they have not been fully explored for the limits of their safety
and efficiency. As the therapeutic benefits of AAV mediated gene therapy will almost always increase with
transduction of a greater number of cells, the safe delivery of high viral doses will likely provide a greater
benefit to patients. However, high AAV doses in non-human primates (NHPs) and in other animal models have
been associated with toxicity. If the mechanisms of these virus-induced problems can be elucidated, it may be
possible to avoid them, so that a greater virus dose can be safely delivered. A mouse model allows for studies
of mechanism that can then be investigated in larger animals. We have found that AAV vectors can harm
ocular cells, in particular, cone photoreceptor cells and the retinal pigment epithelium (RPE) in mice, pigs, and
dogs. This toxicity can lead to loss of retinal neurons and the RPE. Toxicity does not correlate with capsid type,
the “cleanliness” of the stock, the gene that is expressed, or the preparation method. Rather, toxicity tracks
with dose and genome sequence. We propose to identify the sequences that cause, and/or protect, against
this toxicity. We also plan to track the cellular response to these toxic genomic sequences, to identify the cell
type(s) in which toxicity is initiated, as well as the cell types which may amplify the results of viral detection. To
this end, we will explore the RNA changes in several ocular cell types over time following infection with toxic
and non-toxic AAV preparations. We will also follow the mechanism(s) that are triggered by these gene
expression changes, and seek ways to block them. These findings will be extended to the brain, using
injections of toxic and non-toxic stocks into the cerebral cortex. We will assay changes in brain RNA and cell
health, using as probes the changes that we find in the retina. We will also test whether mechanisms that
alleviate toxicity in the retina and in the brain.

## Key facts

- **NIH application ID:** 9902496
- **Project number:** 5R01EY029348-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** CONSTANCE L CEPKO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $416,375
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902496

## Citation

> US National Institutes of Health, RePORTER application 9902496, AAV Induced Toxicity in the Eye (5R01EY029348-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9902496. Licensed CC0.

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