# A Self-Delivery siRNA for Promoting Regenerative Healing in the Eye

> **NIH VA I01** · SYRACUSE VA  MEDICAL CENTER · 2022 · —

## Abstract

Project Summary
Corneal scarring and glaucoma accounts for ocular disability in millions of veterans, active military, and
civilians. Injuries to the eye remain a battlefield and clinical challenge with the potential to severely
reduce vision and quality of life. Ocular trauma and brain injury with resulting visual deficits are major
causes of vision loss among our veterans and troops engaged in Operations Enduring Freedom and
Iraqi Freedom. In addition to acute trauma, aging veterans have a significant increase in age-related
glaucoma compared to the general population. The total cost, including treatment is estimated at 2.4
billion annually for the Armed Services. The link between cornea and glaucoma is that a) almost any
severe eye injury because of the inflammation generated during wound healing and the drugs
administered to treat the inflammation will lead to the onset of glaucoma, and b) the two scarring
indications have similar biological underpinnings and thus it is a cost savings to work on both indications
at the same time. We are proposing the use of a self-delivery siRNA to prevent and reverse scarring in
the cornea and to prevent scarring in the sclera bleb made to reduce intraocular pressure in the eye.
Our self-delivery (modified with cholesterol to gain entry into cells) siRNA modified for in vivo use is
protected with a utility patent to prevent scarring in the eye and a second provisional patent for the
modified self-delivery siRNA sequence and structure.
Acute scarring, similar to chronic fibrosis, is characterized by immune cell infiltration and the persistence
of cells termed myofibroblasts. Pathological myofibroblasts exhibit increased cell adhesion and tissue
contraction through the force generated by binding to the extracellular matrix and the intracellular actin
cytoskeleton via integrins (transmembrane proteins). We have discovered a key point in the healing
pathway that can be therapeutically targeted to control cell apoptosis, immune infiltration, and integrin-
mediated pathological myofibroblast development. Collectively, our studies in primary human corneal
cells, pig corneal organ culture, and in rabbits demonstrate that wounding induces the expression of
the deubiquitinase (DUB), USP10. USP10 removes ubiquitin from both p53 and αv-integrins.
Knockdown of USP10 with one dose of self-delivery siRNA in vivo after corneal wounding significantly
reduced apoptosis, immune infiltration, fibrotic markers, and corneal scarring, and a pilot study
demonstrated regenerative healing in the glaucoma filtration bleb. Towards the goal of realizing the
most effective and specific USP10-targeted therapeutic, in Aim 1, we propose to elucidate the USP10
domains that lead to scarring outcomes and the effect of USP10 binding partner, G3BP2 on USP10
DUB activity. In Aim 2, we will expand our studies on USP10 knockdown to determine if corneal
inflammation and scarring can be totally prevented with a second dose of self-delivery siRNA and
...

## Key facts

- **NIH application ID:** 10406147
- **Project number:** 5I01BX005360-02
- **Recipient organization:** SYRACUSE VA  MEDICAL CENTER
- **Principal Investigator:** AUDREY M BERNSTEIN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406147

## Citation

> US National Institutes of Health, RePORTER application 10406147, A Self-Delivery siRNA for Promoting Regenerative Healing in the Eye (5I01BX005360-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10406147. Licensed CC0.

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