Department of Defense Funds Study of Gene Therapy for Muscular Degeneration

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Example of a Cas9 ribonucleoprotein that would be delivered to fix genetic diseases like Duchenne Muscular Dystrophy.

The U.S. Department of Defense awarded just under $514,000 to an interdisciplinary team of researchers at the U of A to study the efficacy of “self-delivering” gene editors in the treatment of Duchenne Muscular Dystrophy, or DMD. 

DMD results from a mutation in the dystrophin gene and is one of the most severe inherited muscular dystrophies, leading to deterioration of the muscle fibers. Presently, there is no cure, but advances in treatment have helped patients live longer, better lives.

Gene therapy designed to supply replacement genes to skeletal muscles may hold the key to a cure. Current treatment techniques favor a viral delivery of replacement genes, through what’s known as an adeno associated virus, to targeted skeletal muscles. But there are still many unknowns with this form of treatment, including how long a given gene replacement therapy will last, whether the body will counteract the therapy through a strong immune response and whether the gene therapy will result in unintentional genomic changes, which can trigger undesirable side effects.

The researchers will explore non-viral options for delivering gene therapy to potential DMD patients, specifically “self-delivering” gene editors. They are self-delivering in that they would move through the bloodstream into muscle tissues through a process called endothelial transcytosis, rather than using a viral delivery system.

Initial testing will be done through microphysiological systems known as organs-on-chips that can model the endothelial barrier. Endothelial cells line blood vessels and regulate the movement of materials between blood vessels and surrounding tissues. The researchers will study both skeletal muscles cells and muscle stem cells that are responsible for rebuilding muscle.

They hope to identify the best gene editors in terms of safety and efficacy, ideally allowing a wider pool of patients to access these innovative new gene therapies.

Chris Nelson, an assistant professor of biomedical engineering, will be the principal investigator. Nelson’s lab specializes in developing biologically inspired strategies for controlled drug and gene delivery for gene therapy and regenerative medicine. 

Nelson noted that “this project is the result of an exciting collaboration between multiple fields of research.”

This includes Kartik Balachandran, a professor of biomedical engineering, serving as a co-principal investigator. Balachandran specializes in the creation of organs-on-chips — 3D organ constructs engineered from human cells and tissues that mimic critical human functions. Joining them is Kevin Murach, an assistant professor in the Health, Human Performance and Recreation Department, who specializes in the study of skeletal muscle mass regulation, as an additional co-PI.

Nelson noted that Shilpi Agrawal, a postdoctoral researcher in his lab, made important contributions to drafting the award proposal and collecting preliminary data. This is Nelson’s second major grant in recent months, complementing a recent $1.8 million award from the National Institutes of Health.

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