# Technologies to enable safe and effective gene editing in skeletal muscle

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $531,109

## Abstract

Gene editing is moving towards the clinic, but several challenges must be addressed in order for it to be applied
to skeletal muscle disease. Adeno-associated virus (AAV) is one of the most promising technologies to enable
delivery of gene editing machinery to skeletal muscle, but at least four major hurdles stand in the way of using it
to safely and effectively edit genes in this tissue. These include 1) maximizing delivery of editing enzymes to
muscle, 2) maximizing spread of editing enzymes across nuclei of the myofiber syncytium, 3) avoiding sustained
expression of editing enzymes, and 4) integrating solutions to each of these problems in a single AAV so as to
minimize total viral dose required. Given that exciting new myotropic capsids that have emerged in the literature,
this proposal is primarily focused on addressing the latter 3 issues. We have previously developed ways to
shuttle Cas enzymes throughout myofibers and now propose to use creative new approaches that rely on tried-
and-true mechanisms to access and edit even more myonuclei in skeletal muscle. We have also developed ways
to use small molecules to control AAV-delivered gene expression and propose to further develop this technology
to achieve fully “off” transgene states with maximally “on” states when desired, so that Cas enzyme expression
can be turned off when no longer needed. Finally, we will integrate these technologies with the latest miniaturized
Cas enzymes and package all components, including guide RNAs, into a single AAV vector. We will test
approaches in mouse models of myotonic dystrophy and Duchenne muscular dystrophy. Ultimately, the insights
we make here will be apply to gene editing for any skeletal muscle disease and enable the next generation of
therapies for muscular dystrophies.

## Key facts

- **NIH application ID:** 10999595
- **Project number:** 1R01AR084841-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Eric T Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $531,109
- **Award type:** 1
- **Project period:** 2024-09-10 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999595

## Citation

> US National Institutes of Health, RePORTER application 10999595, Technologies to enable safe and effective gene editing in skeletal muscle (1R01AR084841-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10999595. Licensed CC0.

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