# Improving AAV-transduction efficiencies for skeletal muscle delivery

> **NIH NIH R21** · SCRIPPS FLORIDA · 2021 · $277,500

## Abstract

PROJECT SUMMARY
Adeno-associated virus (AAV) is the most commonly used gene therapy vector. Currently, FDA has
approved two AAV-mediated therapies, and many more are in pipeline. However, there still are
challenges to the effective use of AAV vectors. For example, high doses (~1014 vector particles) are
necessary for most human applications. Such high vector doses cause tissue toxicity and elicit high
levels of anti-transgene antibodies, limiting therapeutic efficacy. High doses also require large injection
volumes and/or multiple injections to achieved desired levels of transgene expression. In addition, high
manufacturing costs preclude widespread use of this approach. Each of these difficulties can be
addressed by increasing the efficiency of AAV transduction and thereby reducing the number of AAV
particles necessary to achieve a desired therapeutic outcome.
The intramuscular route of vector delivery has key advantages. It helps circumvent the problem of pre-
existing antibodies to the AAV capsid, which otherwise prevents efficient transduction. Expression of a
transgene from muscle persists for years or decades due the longevity of this tissue. Finally, unlike
other tissues targeted to express AAV transgenes such as the liver, the consequences of tissue
damage through local inflammation are modest and manageable to address. However, the relative
inefficiency with which AAV transduces human and non-human primate muscle tissues necessitates
high vector doses. Therefore many challenges to the AAV-based therapies can be addressed by
improving the efficiency of muscle-specific transduction.
In the Preliminary Studies, we show that AAV9 modified in the variable region VIII with an insulin
receptor-binding peptide is dramatically more efficient than wild-type AAV9 in transducing human
differentiated muscle cells and mouse muscles in vivo. We propose in Aim 1 to further improve this
vector through directed evolution and selection, and to assess the utility of this peptide in the context of
other AAV serotypes. We also propose in Aim 2 to verify our hypotheses that by enhancing vector
efficiency, we can reduce tissue toxicity, inflammation, and anti-transgene antibody production, thereby
increasing the safety and therapeutic efficacy of these vectors. Together, these studies will identify an
AAV vector that much more efficiently transduce muscle tissue, and in doing so, they will also address
several challenges associated with AAV-mediated gene therapy.

## Key facts

- **NIH application ID:** 10127150
- **Project number:** 1R21AI151537-01A1
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Hyeryun Choe
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $277,500
- **Award type:** 1
- **Project period:** 2021-04-15 → 2022-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127150

## Citation

> US National Institutes of Health, RePORTER application 10127150, Improving AAV-transduction efficiencies for skeletal muscle delivery (1R21AI151537-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127150. Licensed CC0.

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