# Development of optimized adeno-associated viral capsids for muscle gene therapy

> **NIH NIH R43** · AAVOGEN, INC. · 2024 · $134,000

## Abstract

PROJECT SUMMARY. Gene therapeutics offer hope to many patients with rare muscle and neuromuscular
diseases. Despite some early successes, several serious off-target safety concerns have compromised their
development due to hepatic toxicities and related immune responses to the adeno-associated viral (AAV)
vectors. The generation of novel capsids with superior muscle specificity could, therefore, revolutionize the
muscle gene therapy space by avoiding the off-target effects that compromise drug efficacy and safety. Our
objective is to engineer novel AAV capsids with muscle tropism that exceeds the current “muscle tropic”
serotypes (e.g. AAV6, AAV8, AAV9, AAVrh74 & MyoAAVs) as none is actually “muscle-specific”. Indeed, all of
these serotypes can transduce other tissues, especially the liver, which is functionally linked to the noted clinical
toxicities. In fact, the liver functions as a sink for these vectors, limiting muscle transduction and elevating the
minimally effective dose. We hypothesize that de-targeting the liver while simultaneously enhancing muscle
tropism is key to improving muscle gene therapy safety and efficacy. Other groups have sought to enhance
muscle tropism using directed evolution. This high throughput method artificially selects capsids with improved
muscle tropism, but cannot also de-target the liver. By contrast, we will use a rational design approach to
simultaneously target known epitopes for liver de-targeting, enhanced AAV-receptor binding and improved
muscle targeting. These include those for improved sialic acid/AAV-receptor binding, impaired liver
targeting/heparin sulfate binding, improved integrin binding and capsids with combined properties. We will also
use AAV6 as liver- and muscle-targeting epitopes are known for this serotype, but not for the other serotypes.
Milestone 1 will develop liver de-targeted/muscle targeted AAV6 capsids using well-established in vivo and in
vitro imaging approaches. Milestone 2 will demonstrate functional efficacy by comparing a Smad7 muscle gene
therapeutic featuring a wild-type AAV6 (AVGN7) to one with a novel optimized AAV6 capsid. These studies are
understandably high risk yet their significance is disproportionately much higher as they will create a liver de-
targeted capsid with improved muscle tropism and as a result, vastly superior safety and efficacy profiles. This
would substantially innovate the muscle gene therapy space primarily by reducing a manufacturing burden that
limits drug use to younger or fewer patients and thus, reducing the overall treatment costs while expanding the
number of potential patient therapies.

## Key facts

- **NIH application ID:** 10897976
- **Project number:** 5R43AR083297-02
- **Recipient organization:** AAVOGEN, INC.
- **Principal Investigator:** Buel Rodgers
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $134,000
- **Award type:** 5
- **Project period:** 2023-08-02 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897976

## Citation

> US National Institutes of Health, RePORTER application 10897976, Development of optimized adeno-associated viral capsids for muscle gene therapy (5R43AR083297-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10897976. Licensed CC0.

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