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E - Disease Models and Clinical Applications -> Musculo-skeletal Diseases

ARCUS-Mediated Excision of the “Hot Spot” Region of the Human Dystrophin Gene for the Treatment of Duchenne Muscular Dystrophy (DMD)

Type: Oral Abstract Session

Presentation Details
Session Title: Late-breaking Abstracts 2
Location: Concourse Hall 152 & 153
Start Time: 5/19/2023 10:30
End Time: 5/19/2023 10:45

Duchenne muscular dystrophy (DMD) is a genetic disorder associated with mutations in the dystrophin gene. In skeletal, smooth, and cardiac muscle tissue, dystrophin stabilizes muscle cells by connecting cytoskeletal actin to the cell membrane-bound dystrophin-associated protein complex. The absence of intact dystrophin protein leads to inflammation, fibrosis, and progressive loss of muscle function and mass. Over time, children with DMD will develop problems walking and breathing, eventually leading to death in the second or third decade of life due to progressive cardiomyopathy and respiratory insufficiency. DMD occurs in 1 in 3,500 to 5,000 male births, and currently there are limited approved therapies available for patients. A gene-editing approach, such as ARCUS, could allow for a single administration of a drug with possible life-long benefits of muscle retention and function. Here, we describe an approach to restore dystrophin function by utilizing a pair of ARCUS nucleases that are delivered by a single AAV. We demonstrate that the nuclease pair can excise a ~0.5Mb mutation “hot spot” region of the dystrophin gene, comprising exons 45-55, resulting in a variant of the dystrophin protein that is functionally competent. Up to 50% of DMD patients contain pathogenic mutations in this region, suggesting this editing strategy could have broad applicability compared to mutation-specific approaches. Here, we report in vivo proof of concept of the dual nuclease approach in a humanized DMD mouse model. Following AAV delivery, we observed the edited dystrophin variant in multiple tissue types including heart, diaphragm, and skeletal muscle, with evidence of the edited dystrophin transcript in PAX7+ cells, a marker for muscle satellite cells. Furthermore, the maximum force output (MFO) of the gastrocnemius muscle in ARCUS-treated animals was significantly improved, reaching 86% of the MFO levels observed in non-diseased, control mice. This proof-of-concept study demonstrates therapeutic potential of an ARCUS gene editing approach for the treatment of DMD and supports ongoing development toward clinical candidate nomination.

Whitney Lewis1, Gary Owens1, Matthew Jordan-Steele1, Nicole W. Heard1, Benjamin Morris1, Emily Manzon1, Cheng-Wei Wang1, Traci Reddick1, Jason Holt1, Dave C. Morris1, Ramzi J. Khairallah2, Christopher W. Ward2, Jennifer Martin2, Cassie Gorsuch1, Kelly Shelton1, Daniel Martin1, Amy Rhoden Smith1, Jeff Smith1, Derek Jantz1

1Precision BioSciences, Durham, NC,2Myologica LLC, New Market, MD
 G. Owens: None.

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