# Restoring Vision with High-Fidelity Nonsense Codon Correction

> **NIH NIH R24** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $1,443,079

## Abstract

PROJECT SUMMARY/ABSTRACT
Nonsense mutations cause approximately 15% of genetically inherited retinopathies and inherited human
diseases in general, accounting for 2.5 to 3 million patients in the U.S. For certain specific genes, nonsense
mutation incidences can be as high as 40%. Because nonsense mutations cause premature termination (PTC)
of protein translation, the disease phenotype is often severe. Currently, there are only a limited number of
therapies for nonsense mutations being tested in human clinical trials, including gene therapy, small molecule
read-through drugs, or genome editing. Associated challenges equal the promises of each of these therapeutic
options. Looking forward, newer technologies may address these hurdles and provide more safe and efficacious
treatments for patients. During protein translation, tRNA functions at the ribosomal site to incorporate a specific
amino acid into the polypeptide sequence. We aim to develop the next generation of nucleic acid therapy based
on anticodon encoding transfer RNA (ace-tRNA) that incorporates the correct wild type amino acid at the site of
a disease-causing nonsense mutation. Because of the many anatomical advantages afforded by the eye, we
seek to test the broad applicability of ace-tRNA therapeutics for nonsense mutations that cause retinopathies
and related blindness due to defects in a variety of genes, including those encoding ion channel proteins.
Specifically we will focus on nonsense mutation in ion channels expressed in photoreceptors (PR) which convert
retinal light inputs and retinal pigment epithelium (RPE), which provide support for PR. These two cell types are
primarily the site of blindness pathogenesis.
In this project, we will:
 1) Develop ace-tRNA therapeutics that target specific nonsense mutations across several PR and RPE ion
channels.
 2) Engineer both viral and non-viral ace-tRNA delivery systems for long-term editing. Using these we will
 determine the functional outcome of ace-tRNA treatment using cultured cells and human iPSC-derived
 RPE and iPSC-PR retinal organoids.
 3) Test both our viral and non-viral ace-tRNA in vivo using mice harboring genetic defects that cause
 blindness in humans; and
 4) Assess the safety and bioavailability of ace-tRNA therapeutics in our preclinical NHP model systems.
There are no FDA-approved therapeutic drugs that target channelopathies because of the complexities
associated with precise post-translational modifications, carefully regulated expression, and assembly. Our
team’s combined expertise in ace-tRNA development, nanomaterial synthesis, human pluripotent stem cell
biology, ion-channel physiology, and pathophysiological model systems is unique and ideally suited to advance
ace-tRNA technology toward clinical trials for a wide range of genetic diseases that cause blindness.

## Key facts

- **NIH application ID:** 10334544
- **Project number:** 5R24EY032434-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Christopher A Ahern
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,443,079
- **Award type:** 5
- **Project period:** 2021-02-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334544

## Citation

> US National Institutes of Health, RePORTER application 10334544, Restoring Vision with High-Fidelity Nonsense Codon Correction (5R24EY032434-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10334544. Licensed CC0.

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