# Mesenchymal stem cell extracellular vesicles for ischemic retinal damage

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $17,186

## Abstract

Central retinal artery occlusion (CRAO) is an ophthalmological emergency with few proven
therapies. Stem cell-based retinal cell replacement is a highly encouraging approach to achieve
retinal neuroprotection and to save vision in retinal diseases. However, with limitations including
few cells integrated, adverse immune responses, and aberrant growth, an alternative cell-free
approach is required. EVs are nano-vesicular bodies that, when endocytosed by target cells,
trigger specific responses. Here, the microRNA (miRNA) cargo of the EVs plays a key role. This
proposal targets restoration of retinal function using engineered MSC-EVs with function-specific
miRNA. Our studies indicate that EVs can rescue retinal cells that have been acutely subjected
to hypoxia or ischemia, the key mechanism that starts cells dying in CRAO. We also found that
hypoxic preconditioning of MSCs resulted in EVs (H-EVs) with enhanced cytoprotective properties
including anti-apoptosis and anti-inflammation. A number of miRNAs overexpressed in the H-EVs
have cytoprotective properties in retinal cells.
 Our central hypothesis is that targeted EV-specific expression of key miRNAs in MSC-EVs
will re-capitulate the anti-apoptosis and anti-inflammatory actions of H-EVs. We designate such
EVs as Functionally Engineered EVs (FEEs). To facilitate clinical translation of MSC-EV therapy,
we identified key knowledge gaps: (1) The relationship between EV miRNA and its anti-apoptotic
properties; (2) EV miRNA and its role in anti-inflammatory actions of MSC-EVs in retina; and (3)
Can MSC-EVs be enhanced for targeted functionality by engineering their miRNA cargo? Aim 1
will produce FEEs overexpressing miR-424 (FEE-424) and 146b (FEE-146b). We will evaluate
their mechanisms of action, and their candidacy for generation of FEEs in retinal ganglion cells,
microglia, Muller cells, and retinal vascular endothelial cells using loss and gain of function studies
in simulated ischemia in vitro. These results will serve as proof-of-principle for development of
FEEs for amelioration of cell damage in the retina. In Aim 2, FEEs containing miR-424 and -146b
will test specific targeting of anti-apoptotic and inflammatory mechanisms in a rodent model of
CRAO. Proposed studies are expected to provide transformative results whereby MSC-EVs are
modified and delivered for retinal protective action after the ischemic event to treat CRAO.
 The Supplement for Diversity will train a graduate student in data collection and analysis,
reviewing literature critically, designing experiments, and presenting and writing research reports.
The goal is for this experience to increase the student’s skills in performing translational basic
science research and to ensure more opportunities for diversification of the scientific workforce.

## Key facts

- **NIH application ID:** 10766045
- **Project number:** 3R01EY033902-01S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** STEVEN ROTH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $17,186
- **Award type:** 3
- **Project period:** 2022-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766045

## Citation

> US National Institutes of Health, RePORTER application 10766045, Mesenchymal stem cell extracellular vesicles for ischemic retinal damage (3R01EY033902-01S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10766045. Licensed CC0.

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