# Improving delivery of therapeutic material to skeletal muscle

> **NIH NIH R61** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $397,500

## Abstract

Project Summary/Abstract
Despite advances in gene therapy, delivery of therapeutic material to a specific tissue remains a challenge.
This proposal tackles the long-standing delivery issue in the gene therapy field by engineering novel vehicles
for muscle tissue. Our approach to this challenge is to harness the activities of the proteins that directly control
myoblast fusion, a process essential for multinucleated skeletal muscle fibers to develop, repair, and
regenerate. Fusion of a myoblast membrane with a myofiber membrane allows entry of the progenitor into the
syncytium, which is a process that, if understood molecularly and properly engineered, could empower delivery
vehicles to transduce muscle. We will leverage our discoveries of Myomaker and Myomerger, which represent
the minimal and essential machinery for myoblast fusion, to engineer enveloped viruses and exosomes into
specific and efficient vehicles that deliver therapeutic material to muscle cells. Evidence for the challenges
associated with muscle gene therapy is the lack of a treatment for genetic muscle diseases such as muscular
dystrophy. Adeno-associated virus (AAV) is the current standard for efficacious skeletal muscle gene therapy,
but the field has had to reconcile an apparent inability to target muscle stem cells, a goal that would likely need
to be achieved for sustained corrective outcomes. The principal rationale of this proposal is that with the
discovery of muscle-specific fusogens, it is time to re-examine the potential of non-AAV vectors such as
lentiviral vectors and non-viral particles (exosomes) as delivery vehicles that could be used with AAV or
independently. Because Myomaker and Myomerger function at the cell surface of myoblasts to drive the
membrane remodeling processes necessary for fusion, we propose that their presence on viral envelopes and
exosomes will increase entry into muscle. In the R61 phase of this project, we will engineer and optimize
Myomaker and Myomerger, or regions of these proteins, on the envelope of viruses and the surface of
exosomes. We will also assess and optimize the ability of these engineered vehicles to drive entry into muscle
and non-muscle tissues in vitro and in vivo. In the R33 phase, we will validate the use of the delivery vehicles
optimized in the R61 phase to test their ability to deliver clinically relevant levels of therapeutic material.
Specifically, we will determine if our optimized delivery vehicles can restore dystrophin and improve muscle
function in the dystrophin-deficient mdx mouse model. Overall, this work promises to open up a new area of
investigation into regenerative medicine by innovating novel delivery vehicles that could be utilized for a myriad
of musculoskeletal conditions.

## Key facts

- **NIH application ID:** 10022097
- **Project number:** 5R61AR076771-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Douglas Paul Millay
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2019-09-20 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022097

## Citation

> US National Institutes of Health, RePORTER application 10022097, Improving delivery of therapeutic material to skeletal muscle (5R61AR076771-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10022097. Licensed CC0.

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