# Novel platform for optimizing AAV transgene expression to improve efficacy of ocular gene therapies

> **NIH NIH R41** · EPIGENOS BIOSCIENCE, INC. · 2022 · $263,372

## Abstract

Abstract
Gene therapy applications based on adeno-associated virus (AAV) have demonstrated promise in clinical
applications for the treatment of diverse genetic diseases highlighted by the recent FDA approval of AAV vector
formulations as new drugs for ocular and neurological diseases. In these instances, along with all applications
of clinical AAV gene therapy to date, constitutive transcription of the therapeutic cassette is employed without
any safeguards in place to modulate transgene production in the targeted tissue. At the mechanistic level, the
AAV vector transduction pathway is not well understood. The episomal AAV vector genomes form circular
monomers and concatemers and a limited number of studies have demonstrated their associations with histones,
transcriptional activators and repressors implying an untapped level of control related to overall transgene
production. These observations suggest that AAV episomes may be restricted for maximal expression and allude
to the ability for targeted approaches for modulating their epigenetic composition to enhance and/or repress AAV
vector transduction.
We recently developed a technology that couples a dCas9-based protein targeting system at a promoter with a
small bifunctional molecule to control gene expression. Spefically, the dCas9-FKBP system was used to
successfully activate epigenetically-silenced endogenous loci (e.g., MyoD1 and CXCR4) in HEK293 cells.
Epigenos Biosciences proposes adding a new functionality, referred as CEMtrol, to AAV modules that will be
designed to mitigate epigenetic dampening of transgene expression to ensure the efficacy of gene therapies will
not be subject to uncontrollable epigenetic regulation. In collaboration with Dr. Matthew Hirsch, who is developing
therapies for ocular diseases, Phase I will focus on developing an AAV that maximizes transgene expression in
cell culture and explant cornea models as a proof-of-concept feasibility study.

## Key facts

- **NIH application ID:** 10385010
- **Project number:** 1R41EY033603-01
- **Recipient organization:** EPIGENOS BIOSCIENCE, INC.
- **Principal Investigator:** Matthew Louis Hirsch
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $263,372
- **Award type:** 1
- **Project period:** 2022-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385010

## Citation

> US National Institutes of Health, RePORTER application 10385010, Novel platform for optimizing AAV transgene expression to improve efficacy of ocular gene therapies (1R41EY033603-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10385010. Licensed CC0.

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